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WO2016064082A2 - Novel aminoalkyl benzothiazepine derivative and use thereof - Google Patents

Novel aminoalkyl benzothiazepine derivative and use thereof Download PDF

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Publication number
WO2016064082A2
WO2016064082A2 PCT/KR2015/009044 KR2015009044W WO2016064082A2 WO 2016064082 A2 WO2016064082 A2 WO 2016064082A2 KR 2015009044 W KR2015009044 W KR 2015009044W WO 2016064082 A2 WO2016064082 A2 WO 2016064082A2
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WO
WIPO (PCT)
Prior art keywords
amino
methyl
methylthio
dibutyl
tetrahydrobenzo
Prior art date
Application number
PCT/KR2015/009044
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French (fr)
Korean (ko)
Other versions
WO2016064082A3 (en
Inventor
정원혁
김승인
지승희
고동현
송석범
이근호
전형진
김동규
김동현
Original Assignee
씨제이헬스케어 주식회사
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Priority to BR112016030599-0A priority Critical patent/BR112016030599B1/en
Priority to US15/506,634 priority patent/US9890129B2/en
Priority to JP2017514289A priority patent/JP6386171B2/en
Priority to CA2951824A priority patent/CA2951824C/en
Priority to RU2017103920A priority patent/RU2679891C2/en
Priority to EP15851901.7A priority patent/EP3210977B1/en
Priority to AU2015336400A priority patent/AU2015336400B8/en
Priority to CN201580044981.2A priority patent/CN106573902B/en
Application filed by 씨제이헬스케어 주식회사 filed Critical 씨제이헬스케어 주식회사
Priority to DK15851901.7T priority patent/DK3210977T3/en
Priority to ES15851901T priority patent/ES2729305T3/en
Priority to MX2016016593A priority patent/MX2016016593A/en
Publication of WO2016064082A2 publication Critical patent/WO2016064082A2/en
Publication of WO2016064082A3 publication Critical patent/WO2016064082A3/en
Priority to IL250668A priority patent/IL250668B/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D281/02—Seven-membered rings
    • C07D281/04—Seven-membered rings having the hetero atoms in positions 1 and 4
    • C07D281/08—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D281/10—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/10—Laxatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C13/00—Cyclic hydrocarbons containing rings other than, or in addition to, six-membered aromatic rings
    • C07C13/02—Monocyclic hydrocarbons or acyclic hydrocarbon derivatives thereof
    • C07C13/24—Monocyclic hydrocarbons or acyclic hydrocarbon derivatives thereof with a seven-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C13/00—Cyclic hydrocarbons containing rings other than, or in addition to, six-membered aromatic rings
    • C07C13/28—Polycyclic hydrocarbons or acyclic hydrocarbon derivatives thereof
    • C07C13/32—Polycyclic hydrocarbons or acyclic hydrocarbon derivatives thereof with condensed rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/02—Sulfones; Sulfoxides having sulfone or sulfoxide groups bound to acyclic carbon atoms
    • C07C317/06—Sulfones; Sulfoxides having sulfone or sulfoxide groups bound to acyclic carbon atoms of a saturated carbon skeleton containing rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D281/02—Seven-membered rings
    • C07D281/04—Seven-membered rings having the hetero atoms in positions 1 and 4
    • C07D281/08—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the present invention relates to a novel aminoalkylbenzothiazepine derivative or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition for preventing or treating constipation comprising the same as an active ingredient.
  • Constipation is a common digestive disease with a prevalence of about 16% in Korea. It is more common in women than men and increases in older people with a prevalence of about 30 to 40%. Constipation is unpleasant and has a profound effect on daily life, making it the second most common reason for absenteeism in the West, and also reporting severely declining quality of life.
  • Stimulant laxative is to block the absorption of water in the colon and stimulate the movement of the colon, senna (senna) and bisacodyl (bisacodyl) and the like are widely used.
  • the stool softener is to increase the water absorption of the stool by lowering the surface tension of the stool, there is typically a ducocate (ducosate).
  • these irritant laxatives and stool softeners are not effective for long periods of time because of their short-term efficacy and resistance to expression.
  • Bile acids are made from cholesterol in the liver and stored in the gallbladder and then released into the small intestine to help digest digestive nutrients such as lipids and lipids. Bile acids migrate to the lower intestine and 90% are reabsorbed by the liver. Inhibition of bile acid resorption by drugs causes bile acids to move to the large intestine, which in turn stimulates the secretion of water and promotes the movement of the colon, which is useful for the treatment and prevention of constipation. .
  • the present inventors have conducted research to discover novel compounds that can be used for the prevention or treatment of constipation.
  • a series of aminoalkylbenzothiazepine derivatives can be effectively used for the prevention or treatment of constipation by effectively inhibiting the resorption of bile acids. It was confirmed that the present invention was completed.
  • One object of the present invention is to provide a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof:
  • Another object of the present invention to provide a pharmaceutical composition for the prevention or treatment of constipation comprising the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • novel aminoalkylbenzothiazepine derivative compounds of the present invention inhibit bile acid resorption, thereby causing bile acids to migrate to the large intestine, leading to the promotion of water secretion and colon movement in the large intestine.
  • the present invention provides a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof:
  • R 1 is hydroxy, carboxy or hydroxysulfonyl (C 1-4 alkyl);
  • R 2 and R 3 are each independently hydrogen, C 1-4 alkyl, hydroxy (C 1-4 alkyl), carbamoyl (C 1-4 alkyl), carboxy, carboxy (C 1-4 alkyl), (C 5-10 heteroaryl) (C 1-4 alkyl) or (C 5-10 aryl) (C 1-4 alkyl) or R 2 and R 3 together form C 3-7 cycloalkyl;
  • R 4 is hydrogen or carboxy (C 1-4 alkyl);
  • R 5 is hydrogen, halogen, (C 1-4 alkyl) thio, (C 1-4 alkyl) amino or di (C 1-4 alkyl) amino;
  • R 6 and R 7 are each independently C 1-6 alkyl
  • R 8 and R 9 are each independently hydrogen, hydroxy, C 1-4 alkoxy, C 1-4 alkyl, halogen, nitro, cyano, amino, (C 1-4 alkyl) amino, di (C 1-4 Alkyl) amino, acetamido, formyl, C 1-4 alkanoyl, carboxy, carbamoyl, (C 1-4 alkyl) carbamoyl, di (C 1-4 alkyl) carbamoyl, carbamoyloxy, (C 1-4 alkyl) carbamoyloxy, di (C 1-4 alkyl) carbamoyloxy, (C 1-4 alkyl) sulfonyloxy, sulfamoyloxy, (C 1-4 alkyl) sulfamoyloxy or di (C 1-4 alkyl) sulfamoyloxy;
  • Q is C 5-10 aryl or C 5-10 heteroaryl
  • n is an integer of 0-3.
  • R 1 is hydroxy, carboxy or hydroxysulfonyl (C 1-4 alkyl);
  • R 2 and R 3 are each independently hydrogen, C 1-4 alkyl, hydroxy (C 1-4 alkyl), carbamoyl (C 1-4 alkyl), carboxy, carboxy (C 1-4 alkyl) or (C 5-10 heteroaryl) (C 1-4 alkyl) or R 2 and R 3 together form C 3-7 cycloalkyl;
  • R 4 is hydrogen or carboxy (C 1-4 alkyl);
  • R 5 is (C 1-4 alkyl) thio
  • R 6 and R 7 are each independently C 1-6 alkyl
  • R 8 and R 9 are each independently hydrogen, hydroxy, halogen or C 1-4 alkoxy
  • Q is C 5-10 aryl
  • n may be an integer from 0 to 3.
  • R 1 may be hydroxy, carboxy or hydroxysulfonylmethyl.
  • R 2 and R 3 are each independently hydrogen, carboxy, methyl, isobutyl, carbamoylmethyl, carboxymethyl, carboxyethyl, hydroxymethyl, imidazolylmethyl, indolylmethyl or ethyl, or R 2 and R 3 together may form cyclopropyl.
  • R 4 may be hydrogen, carboxymethyl or carboxyethyl.
  • R 5 may be methylthio, ethylthio or dimethylamino.
  • R 6 and R 7 may both be butyl or ethyl.
  • R 8 and R 9 are each independently hydrogen, hydroxy, methoxy, methyl, ethyl, fluoro, chloro, nitro, cyano, amino, methylamino, ethylamino, dimethylamino, acetyl, carboxy , Carbamoyl, methylcarbamoyl, dimethylcarbamoyl, carbamoyloxy, methylcarbamoyloxy, dimethylcarbamoyloxy, methylsulfonyloxy, sulfamoyloxy, methylsulfamoyloxy or dimethylsulfamoyloxy.
  • Q may be phenyl, pyridine, pyrimidine or thiophene.
  • Q may be phenyl, pyridine, pyrimidine or thiophene substituted with R 8 and R 9 .
  • R 8 and R 9 are positioned on different elements, and other positions may be bonded to hydrogen.
  • R 8 and R 9 are both hydrogen, it means that Q is unsubstituted phenyl, pyridine, pyrimidine or thiophene.
  • the compounds of the present invention may exist in the form of pharmaceutically acceptable salts.
  • salts are acid salts formed with pharmaceutically acceptable free acids.
  • pharmaceutically acceptable salt of the present invention is any concentration of the compound which is relatively nontoxic to the patient and has a harmless effective action, in which the side effects caused by the salt do not degrade the beneficial efficacy of the compound represented by the formula (1). Means any organic or inorganic addition salt.
  • Acid addition salts can be prepared by conventional methods, for example by dissolving a compound in an excess of aqueous acid solution and precipitating the salt using a water miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. Equivalent molar amounts of the compound and acid or alcohol (eg, glycol monomethyl ether) in water can be heated and the mixture can then be evaporated to dryness or the precipitated salts can be suction filtered.
  • a water miscible organic solvent such as methanol, ethanol, acetone or acetonitrile.
  • Equivalent molar amounts of the compound and acid or alcohol (eg, glycol monomethyl ether) in water can be heated and the mixture can then be evaporated to dryness or the precipitated salts can be suction filtered.
  • Bases can also be used to make pharmaceutically acceptable metal salts.
  • Alkali metal salts or alkaline earth metal salts are obtained, for example, by dissolving a compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and then evaporating and drying the filtrate.
  • salts of the compounds of the present invention include salts of acidic or basic groups which may be present in the compound of Formula 1, and may be prepared through methods of preparing salts known in the art. have.
  • the compounds of the present invention have asymmetric carbon centers in the parent nucleus and its substituents and therefore may exist as R or S isomers, racemates, diastereomeric mixtures and individual diastereomers, all of these isomers and mixtures thereof. It is included in the scope of the invention.
  • the compounds of the present invention can be synthesized from amino-alkoxybenzenethiol and 3-bromo-2- (mono or di) alkylpropanoic acid through a series of reactions represented by Scheme 1 below.
  • Scheme 1 the following reaction scheme is merely an exemplary method for preparing the compound of the present invention, and the method for preparing the compound of the present invention is not limited thereto, and may be performed by using a method known in the art or by appropriately changing it.
  • step 1 is an amino-alkoxybenzenethiol (eg, amino-methoxybenzenethiol) which is a compound represented by the formula (2) and 3-bromo-2- (mono or di) alkylpropanoic acid derivative represented by the formula (3).
  • Reacting for example, 3-bromo-2,2-dibutylpropanoic acid aka 2-bromomethyl-2-butylhexanoic acid
  • the reaction of may be carried out in the presence of potassium hydroxide, water may be used as a solvent, but is not limited thereto.
  • Step 2 is a cyclization reaction for forming benzothiazepine, wherein the compound represented by Formula 4 prepared in Step 1 is prepared by HATU (1- [bis (dimethylamino) methylene] -1H-1,2,3-tria 3,3-dialkyl-8-alkoxy-2,3-dihydrobenzo [b] [1 represented by the formula (5) by reacting with zolo [4,5-b] pyridinium 3-oxide hexafluorophosphate) , 4] thiazepin-4 (5H) -one derivative.
  • dichloromethane may be used as the solvent of step 2, but is not limited thereto.
  • Step 3 is a step of introducing a bromo group as a reactive substituent, 7-bromo-3,3 represented by the formula (6) by reacting the compound represented by the formula (5) prepared in step 2 with N-bromosuccinimide -Dialkyl-8-alkoxy-2,3-dihydrobenzo [b] [1,4] thiazepin-4 (5H) -one derivative.
  • N-bromosuccinimide -Dialkyl-8-alkoxy-2,3-dihydrobenzo [b] [1,4] thiazepin-4 (5H) -one derivative.
  • dichloromethane may be used as the solvent of step 3, but is not limited thereto.
  • N-bromosuccinimide N-halosuccinimide containing another halogen element can be used.
  • the salogen element may be used without limitation as long as it can provide a substituent capable of exhibiting sufficient reactivity in the subsequent substitution reaction.
  • Step 4 is a step of introducing a substituent on the nitrogen atom of the thiazepine ring, it can be achieved by reacting the compound represented by the formula (6) prepared from step 3 with the iodide compound represented by the formula (7).
  • the reaction of step 4 may be carried out in the presence of CuI, xylene may be used as the solvent, but is not limited thereto.
  • Step 5 is a step of removing the ketone group on the tiazine ring by a reduction reaction
  • LiAlH 4 may be used as the reducing agent, but is not limited thereto.
  • Reducing agents capable of converting -groups to -CH 2 -can be used without limitation.
  • diethyl ether may be used as the solvent of step 5, but is not limited thereto.
  • Step 6 is a step of preparing a dioxide derivative of thiazepine by oxidizing with osmium tetroxide.
  • a mixed solvent of tetrahydrofuran and t-butanol may be used as the solvent of step 6, but is not limited thereto. .
  • Step 7 is a step of introducing a substituent R 5 at a position where a reactive halogen is substituted by a substitution reaction, and simultaneously converting an alkoxy group on a benzo ring to a hydroxyl group.
  • a metal salt of a substituent to be introduced such as an alkali
  • Metal salts MR 5 ; M is an alkali metal
  • DMF dimethylformamide
  • Step 8 converts the hydroxy group on the benzo ring to trifluoromethanesulfonate (aka triflate; OTf), which is a good leaving group.
  • the reactant for introducing OTf is trifluoromethanesulphonic Hydride (TfO 2 ) can be used.
  • TfO 2 trifluoromethanesulphonic Hydride
  • dichloromethane may be used as the solvent of step 8, but is not limited thereto.
  • Step 9 is a step of introducing a cyano group as a precursor of the aminomethyl group, the step of replacing the OTf group with a CN group by reacting the compound represented by the formula (13) to which the OTf group prepared from the above step 8 is introduced with zinc cyanide.
  • the reaction of Step 1 may be carried out in the presence of palladium, dimethylformamide may be used as the solvent, but is not limited thereto.
  • Step 10 is a step of converting the cyano group to formyl by reacting a compound introduced with a cyano group through step 9 with diisobutylaluminum hydride (DIBAL-H).
  • DIBAL-H diisobutylaluminum hydride
  • dichloromethane may be used as the solvent of step 10, but is not limited thereto.
  • Step 11 is a step of condensing the compound represented by Formula 15 prepared in Step 10 with an amine derivative to obtain the title compound.
  • the reaction of step 11 may be carried out in the presence of sodium triacetoxyborohydride (NaB (OAc) 3 H), dichloroethane may be used as a solvent, but is not limited thereto.
  • NaB (OAc) 3 H sodium triacetoxyborohydride
  • dichloroethane may be used as a solvent, but is not limited thereto.
  • the present invention provides a pharmaceutical composition for the prevention or treatment of constipation comprising the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • prevention means any action that inhibits or delays the occurrence, spread and recurrence of constipation by administration of the pharmaceutical composition
  • treatment refers to the disease by administration of the pharmaceutical composition. Means any action that improves or beneficially changes the condition of
  • the pharmaceutical composition according to the present invention may contain the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient, and may further include a pharmaceutically acceptable carrier, diluent or excipient.
  • composition of the present invention is administered in a pharmaceutically effective amount.
  • pharmaceutically effective amount means an amount sufficient to treat the disease at a reasonable benefit / risk ratio applicable to the medical treatment and not causing side effects, and the term “administration” of the present invention may be any Means providing the patient with the desired material in an appropriate manner.
  • terapéuticaally effective amount as used in combination with an active ingredient in the present invention means an amount of an aminoalkylbenzothiazepine derivative compound or a pharmaceutically acceptable salt thereof effective for preventing or treating a subject disease.
  • the pharmaceutical composition of the present invention is a known drug used for the prevention or treatment of each disease other than an aminoalkylbenzothiazepine derivative compound or a pharmaceutically acceptable salt thereof as an active ingredient, depending on the type of disease to be prevented or treated. It may further include.
  • 6-methoxybenzo [d] thiazol-2-amine 25 g, 139.7 mmol was added to 250 mL of 30% potassium hydroxide and stirred at 140 ° C. for 18 hours. After checking the reaction solution by TLC to confirm the formation of 2-amino-5-methoxybenzenethiol, the reaction solution was cooled to room temperature. Then 2-bromomethyl-2-butylhexanoic acid (44.6 g, 167.7 mmol) was added and stirred at room temperature for about 17 hours. After adding saturated ammonium chloride solution and dichloromethane and stirring for 10 minutes, the process of extracting the dichloromethane layer was repeated three times.
  • Example 1 2 -(((3,3- Dibutyl -7- Methylthio -1,1- Deoxydo -5-phenyl-2,3,4,5- Tetrahydrobenzo [b] [1,4] thiazepine Preparation of -8-yl) methyl) amino) acetic acid
  • Example 8 2 -(((3,3- Dibutyl -7- Methylthio -1,1- Deoxydo -5-phenyl-2,3,4,5- Tetrahydrobenzo [b] [1,4] thiazepine Preparation of -8-yl) methyl) amino) -2-methylpropanoic acid
  • Example 14 3 -(( Carboxymethyl ) ((3,3- Dibutyl -7- Methylthio -1,1- Deoxydo Preparation of -5-phenyl-2,3,4,5-tetrahydrobenzo [b] [1,4] thiazepin-8-yl) methyl) amino) propanoic acid
  • Example 15 3 -(((3,3- Dibutyl -7- Methylthio -1,1- Deoxydo -5-phenyl-2,3,4,5- Tetrahydrobenzo [b] [1,4] thiazepine Preparation of -8-yl) methyl) amino) pentanedioic acid
  • Example 16 2 -(((3,3- Dibutyl -7- Methylthio -1,1- Deoxydo -5-phenyl-2,3,4,5- Tetrahydrobenzo [b] [1,4] thiazepine Preparation of -8-yl) methyl) amino) -2-oxoacetic acid
  • Example 17 1 -(((3,3- Dibutyl -7- Methylthio -1,1- Deoxydo -5-phenyl-2,3,4,5- Tetrahydrobenzo [b] [1,4] thiazepine Preparation of -8-yl) methyl) amino) cyclopropanecarboxylic acid
  • Example 18 2 -(((3,3- Dibutyl -7- Methylthio -1,1- Deoxydo -5-phenyl-2,3,4,5- Tetrahydrobenzo [b] [1,4] thiazepine Preparation of -8-yl) methyl) amino) -2-oxoethanesulfonic acid
  • Example 19 2 -(((3,3- Dibutyl -5- (4- Methoxyphenyl ) -7- Methylthio -1,1- Deoxydo Preparation of -2,3,4,5-tetrahydrobenzo [b] [1,4] thiazepin-8-yl) methyl) amino) acetic acid
  • Example 20 2 -(((3,3- Dibutyl -5- (4- Hydroxyphenyl ) -7- Methylthio -1,1- Deoxydo Preparation of -2,3,4,5-tetrahydrobenzo [b] [1,4] thiazepin-8-yl) methyl) amino) acetic acid
  • Example 21 2 -(((3,3- Dibutyl -5- (3- Methoxyphenyl ) -7- Methylthio -1,1- Deoxydo Preparation of -2,3,4,5-tetrahydrobenzo [b] [1,4] thiazepin-8-yl) methyl) amino) acetic acid
  • Example 22 2 -(((3,3- Dibutyl -5- (4- Fluorophenyl ) -7- Methylthio -1,1- Deoxydo Preparation of -2,3,4,5-tetrahydrobenzo [b] [1,4] thiazepin-8-yl) methyl) amino) acetic acid
  • Example 23 2 -(((3,3- Dibutyl -5- (3- Fluorophenyl ) -7- Methylthio -1,1- Deoxydo Preparation of -2,3,4,5-tetrahydrobenzo [b] [1,4] thiazepin-8-yl) methyl) amino) acetic acid
  • Example 24 2-(((3,3-dibutyl-5- (3-fluoro-4-methoxyphenyl) -7-methylthio-1,1-dioxido-2,3,4,5- Preparation of tetrahydrobenzo [b] [1,4] thiazepin-8-yl) methyl) amino) acetic acid
  • the title compound was prepared in a similar manner to the preparation of the compound of Example 1, except that 2-fluoro-4-iodo-1-methoxybenzene was used instead of iodoated benzene in step 3 of Preparation Example 1. Synthesized.
  • Example 25 2-(((3,3-dibutyl-5- (4-methoxyphenyl) -7-methylthio-1,1-dioxido-2,3,4,5-tetrahydrobenzo [b ] [1,4] thiazepin-8-yl) methyl) amino) -2-oxoethanesulfonic acid
  • Example 26 1-(((3,3-dibutyl-5- (3-fluoro-4-methoxyphenyl) -7-methylthio-1,1-dioxido-2,3,4,5- Preparation of tetrahydrobenzo [b] [1,4] thiazepin-8-yl) methyl) amino) cyclopropanecarboxylic acid
  • Example 27 2 -(((3,3- Dibutyl -5- (4- Fluorophenyl ) -7- Methylthio -1,1- Deoxydo Preparation of -2,3,4,5-tetrahydrobenzo [b] [1,4] thiazepin-8-yl) methyl) amino) -2-oxoacetic acid
  • Example 28 (S) -2-(((3,3- Dibutyl -5- (4- Fluorophenyl ) -7- Methylthio -1,1- Deoxydo Preparation of -2,3,4,5-tetrahydrobenzo [b] [1,4] thiazepin-8-yl) methyl) amino) propanoic acid
  • Example 30 1-(((3,3-dibutyl-5- (4-fluorophenyl) -7-methylthio-1,1-dioxido-2,3,4,5-tetrahydrobenzo [b ] [1,4] thiazepin-8-yl) methyl) amino) cyclopropanecarboxylic acid
  • 8-week-old SD rats were purchased and allowed to acclimate for 7 days at 24 ° C. in a 12 hour illuminated breeding environment. Fasting was performed for 16 hours the day before the test, and the test substance prepared at vehicle (0.5% methylcellulose) and 0.2 mg / ml concentration was administered orally at a dose of 5 mg / kg each on the test day. After 30 minutes, rats orally administered 3 g of a barium-containing diet were placed in a metabolic cage and recorded for 10 hours for each barium to be discharged into the stool through the intestine. In addition, the ratio of the individuals who discharged the barium stools in 10 hours is shown in Table 1 together.

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Abstract

The present invention relates to a novel aminoalkyl benzothiazepine derivative or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition, containing the same as an active ingredient, for preventing or treating constipation.

Description

신규한 아미노알킬벤조티아제핀 유도체 및 이의 용도Novel aminoalkylbenzothiazepine derivatives and uses thereof
본 발명은 신규한 아미노알킬벤조티아제핀 유도체 또는 이의 약학적으로 허용 가능한 염, 및 이를 유효성분으로 포함하는 변비의 예방 또는 치료용 약학적 조성물에 관한 것이다.The present invention relates to a novel aminoalkylbenzothiazepine derivative or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition for preventing or treating constipation comprising the same as an active ingredient.
변비는 국내에서 약 16%의 유병률을 보일 정도로 흔한 소화기 질환이다. 남성보다 여성에서 더 많이 발생하며 노인층에서는 더욱 증가하여 유병률은 약 30 내지 40% 정도이다. 변비는 불쾌감을 주고 일상생활에 지대한 영향을 미쳐, 서양에서는 결근 이유의 두 번째로 조사되고 있으며, 또한 삶의 질이 심각히 저하되는 환자들도 보고되고 있다.Constipation is a common digestive disease with a prevalence of about 16% in Korea. It is more common in women than men and increases in older people with a prevalence of about 30 to 40%. Constipation is unpleasant and has a profound effect on daily life, making it the second most common reason for absenteeism in the West, and also reporting severely declining quality of life.
현재 변비약으로는 자극성 하제 및 대변연화제 등이 널리 사용되고 있다. 자극성 하제는 대장 내 수분 흡수를 막고 대장 운동을 자극하는 것으로, 센나(senna) 및 비사코딜(bisacodyl) 등이 널리 사용된다. 또한, 대변연화제는 대변의 표면 장력을 낮추어 대변의 수분 흡수를 증가시키는 것으로, 대표적으로 듀코케이트(ducosate) 등이 있다. 그러나, 이들 자극성 하제 및 대변연화제는 효능이 일시적이고, 내성이 발현될 수 있는 단점이 있어 장기간 사용이 불가하다.Current laxatives include irritant laxatives and stool softeners. Stimulant laxative is to block the absorption of water in the colon and stimulate the movement of the colon, senna (senna) and bisacodyl (bisacodyl) and the like are widely used. In addition, the stool softener is to increase the water absorption of the stool by lowering the surface tension of the stool, there is typically a ducocate (ducosate). However, these irritant laxatives and stool softeners are not effective for long periods of time because of their short-term efficacy and resistance to expression.
한편, 담즙산은 간에서 콜레스테롤로부터 만들어지며 담낭에 보관되다가 식후 지질 및 지질비타민과 같은 영양분의 소화를 돕기 위하여 소장으로 배출된다. 담즙산은 소장 하부로 이동하다가 90%가 간으로 재흡수된다. 약물에 의한 담즙산 재흡수의 억제는 담즙산을 대장으로 이동하게 하여, 대장 내 물분비와 대장운동 촉진을 유발하므로 변비의 치료 및 예방에 유용하다(American Journal of Gastroenterology, 2011, 106: 2154-2163).Bile acids, on the other hand, are made from cholesterol in the liver and stored in the gallbladder and then released into the small intestine to help digest digestive nutrients such as lipids and lipids. Bile acids migrate to the lower intestine and 90% are reabsorbed by the liver. Inhibition of bile acid resorption by drugs causes bile acids to move to the large intestine, which in turn stimulates the secretion of water and promotes the movement of the colon, which is useful for the treatment and prevention of constipation. .
본 발명자들은 변비의 예방 또는 치료에 사용될 수 있는 신규한 화합물을 발굴하기 위하여 연구 노력한 결과, 일련의 아미노알킬벤조티아제핀 유도체가 담즙산의 재흡수를 효과적으로 억제함으로서 변비의 예방 또는 치료에 유용하게 사용될 수 있음을 확인하고 본 발명을 완성하였다.The present inventors have conducted research to discover novel compounds that can be used for the prevention or treatment of constipation. As a result, a series of aminoalkylbenzothiazepine derivatives can be effectively used for the prevention or treatment of constipation by effectively inhibiting the resorption of bile acids. It was confirmed that the present invention was completed.
본 발명의 하나의 목적은 하기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을 제공하는 것이다:One object of the present invention is to provide a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof:
[화학식 1][Formula 1]
Figure PCTKR2015009044-appb-I000001
.
Figure PCTKR2015009044-appb-I000001
.
본 발명의 다른 하나의 목적은 상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 변비의 예방 또는 치료용 약학적 조성물을 제공하는 것이다.Another object of the present invention to provide a pharmaceutical composition for the prevention or treatment of constipation comprising the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명의 신규한 아미노알킬벤조티아제핀 유도체 화합물은 담즙산의 재흡수를 억제함으로서 담즙산이 대장으로 이동하게 하여, 대장 내 물분비와 대장운동의 촉진을 유도한다. 이러한 결과는 본 발명의 화합물이 변비를 효과적으로 치료 및 예방하는데 유용하게 사용될 수 있음을 나타내는 것이다.The novel aminoalkylbenzothiazepine derivative compounds of the present invention inhibit bile acid resorption, thereby causing bile acids to migrate to the large intestine, leading to the promotion of water secretion and colon movement in the large intestine. These results indicate that the compounds of the present invention can be usefully used to effectively treat and prevent constipation.
하나의 양태로서, 본 발명은 하기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을 제공한다:In one embodiment, the present invention provides a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof:
[화학식 1][Formula 1]
Figure PCTKR2015009044-appb-I000002
Figure PCTKR2015009044-appb-I000002
상기 식에서,Where
R1은 히드록시, 카복시 또는 히드록시설포닐(C1-4 알킬)이고;R 1 is hydroxy, carboxy or hydroxysulfonyl (C 1-4 alkyl);
R2 및 R3은 각각 독립적으로 수소, C1-4 알킬, 히드록시(C1-4 알킬), 카바모일(C1-4 알킬), 카복시, 카복시(C1-4 알킬), (C5-10 헤테로아릴)(C1-4 알킬) 또는 (C5-10 아릴)(C1-4 알킬)이거나, R2 및 R3이 함께 C3-7 사이클로알킬을 형성하고;R 2 and R 3 are each independently hydrogen, C 1-4 alkyl, hydroxy (C 1-4 alkyl), carbamoyl (C 1-4 alkyl), carboxy, carboxy (C 1-4 alkyl), (C 5-10 heteroaryl) (C 1-4 alkyl) or (C 5-10 aryl) (C 1-4 alkyl) or R 2 and R 3 together form C 3-7 cycloalkyl;
R4는 수소 또는 카복시(C1-4 알킬)이고;R 4 is hydrogen or carboxy (C 1-4 alkyl);
R5는 수소, 할로겐, (C1-4 알킬)티오, (C1-4 알킬)아미노 또는 디(C1-4 알킬)아미노이고;R 5 is hydrogen, halogen, (C 1-4 alkyl) thio, (C 1-4 alkyl) amino or di (C 1-4 alkyl) amino;
R6 및 R7은 각각 독립적으로 C1-6 알킬이고;R 6 and R 7 are each independently C 1-6 alkyl;
R8 및 R9는 각각 독립적으로 수소, 히드록시, C1-4 알콕시, C1-4 알킬, 할로겐, 니트로, 시아노, 아미노, (C1-4 알킬)아미노, 디(C1-4 알킬)아미노, 아세트아미도, 포르밀, C1-4 알카노일, 카복시, 카바모일, (C1-4 알킬)카바모일, 디(C1-4 알킬)카바모일, 카바모일옥시, (C1-4 알킬)카바모일옥시, 디(C1-4 알킬)카바모일옥시, (C1-4 알킬)설포닐옥시, 설파모일옥시, (C1-4 알킬)설파모일옥시 또는 디(C1-4 알킬)설파모일옥시이고;R 8 and R 9 are each independently hydrogen, hydroxy, C 1-4 alkoxy, C 1-4 alkyl, halogen, nitro, cyano, amino, (C 1-4 alkyl) amino, di (C 1-4 Alkyl) amino, acetamido, formyl, C 1-4 alkanoyl, carboxy, carbamoyl, (C 1-4 alkyl) carbamoyl, di (C 1-4 alkyl) carbamoyl, carbamoyloxy, (C 1-4 alkyl) carbamoyloxy, di (C 1-4 alkyl) carbamoyloxy, (C 1-4 alkyl) sulfonyloxy, sulfamoyloxy, (C 1-4 alkyl) sulfamoyloxy or di (C 1-4 alkyl) sulfamoyloxy;
Q는 C5-10 아릴 또는 C5-10 헤테로아릴이고;Q is C 5-10 aryl or C 5-10 heteroaryl;
n은 0 내지 3의 정수이다.n is an integer of 0-3.
바람직하게, 상기 식에서,Preferably, in the above formula,
R1은 히드록시, 카복시 또는 히드록시설포닐(C1-4 알킬)이고;R 1 is hydroxy, carboxy or hydroxysulfonyl (C 1-4 alkyl);
R2 및 R3은 각각 독립적으로 수소, C1-4 알킬, 히드록시(C1-4 알킬), 카바모일(C1-4 알킬), 카복시, 카복시(C1-4 알킬) 또는 (C5-10 헤테로아릴)(C1-4 알킬)이거나, R2 및 R3이 함께 C3-7 사이클로알킬을 형성하고;R 2 and R 3 are each independently hydrogen, C 1-4 alkyl, hydroxy (C 1-4 alkyl), carbamoyl (C 1-4 alkyl), carboxy, carboxy (C 1-4 alkyl) or (C 5-10 heteroaryl) (C 1-4 alkyl) or R 2 and R 3 together form C 3-7 cycloalkyl;
R4는 수소 또는 카복시(C1-4 알킬)이고;R 4 is hydrogen or carboxy (C 1-4 alkyl);
R5는 (C1-4 알킬)티오이고;R 5 is (C 1-4 alkyl) thio;
R6 및 R7은 각각 독립적으로 C1-6 알킬이고;R 6 and R 7 are each independently C 1-6 alkyl;
R8 및 R9는 각각 독립적으로 수소, 히드록시, 할로겐 또는 C1-4 알콕시이고;R 8 and R 9 are each independently hydrogen, hydroxy, halogen or C 1-4 alkoxy;
Q는 C5-10 아릴이고;Q is C 5-10 aryl;
n은 0 내지 3의 정수일 수 있다.n may be an integer from 0 to 3.
바람직하게, 상기 식에서 R1은 히드록시, 카복시 또는 히드록시설포닐메틸일 수 있다.Preferably, in the above formula R 1 may be hydroxy, carboxy or hydroxysulfonylmethyl.
바람직하게, 상기 식에서 R2 및 R3은 각각 독립적으로 수소, 카복시, 메틸, 이소부틸, 카바모일메틸, 카복시메틸, 카복시에틸, 히드록시메틸, 이미다졸릴메틸, 인돌릴메틸 또는 에틸이거나, R2 및 R3이 함께 사이클로프로필을 형성할 수 있다.Preferably, wherein R 2 and R 3 are each independently hydrogen, carboxy, methyl, isobutyl, carbamoylmethyl, carboxymethyl, carboxyethyl, hydroxymethyl, imidazolylmethyl, indolylmethyl or ethyl, or R 2 and R 3 together may form cyclopropyl.
바람직하게, 상기 식에서 R4는 수소, 카복시메틸 또는 카복시에틸일 수 있다.Preferably, in the above formula R 4 may be hydrogen, carboxymethyl or carboxyethyl.
바람직하게, 상기 식에서 R5는 메틸티오, 에틸티오 또는 디메틸아미노일 수 있다.Preferably, in the above formula R 5 may be methylthio, ethylthio or dimethylamino.
바람직하게, 상기 식에서 R6 및 R7은 모두 부틸 또는 에틸일 수 있다.Preferably, in the above formula, R 6 and R 7 may both be butyl or ethyl.
바람직하게, 상기 식에서 R8 및 R9는 각각 독립적으로 수소, 히드록시, 메톡시, 메틸, 에틸, 플루오로, 클로로, 니트로, 시아노, 아미노, 메틸아미노, 에틸아미노, 디메틸아미노, 아세틸, 카복시, 카바모일, 메틸카바모일, 디메틸카바모일, 카바모일옥시, 메틸카바모일옥시, 디메틸카바모일옥시, 메틸설포닐옥시, 설파모일옥시, 메틸설파모일옥시 또는 디메틸설파모일옥시일 수 있다.Preferably, wherein R 8 and R 9 are each independently hydrogen, hydroxy, methoxy, methyl, ethyl, fluoro, chloro, nitro, cyano, amino, methylamino, ethylamino, dimethylamino, acetyl, carboxy , Carbamoyl, methylcarbamoyl, dimethylcarbamoyl, carbamoyloxy, methylcarbamoyloxy, dimethylcarbamoyloxy, methylsulfonyloxy, sulfamoyloxy, methylsulfamoyloxy or dimethylsulfamoyloxy.
바람직하게, 상기 식에서 Q는 페닐, 피리딘, 피리미딘 또는 티오펜일 수 있다. 상기 화학식 1에 따라 Q는 R8 및 R9로 치환된 페닐, 피리딘, 피리미딘 또는 티오펜일 수 있다. 상기 Q에서 R8 및 R9의 위치는 정해지지 않았으나, 서로 다른 원소 상에 위치하며, 이외의 위치는 수소가 결합될 수 있다. 따라서, R8 및 R9가 모두 수소인 경우는 Q가 치환되지 않은 페닐, 피리딘, 피리미딘 또는 티오펜임을 의미한다.Preferably, Q may be phenyl, pyridine, pyrimidine or thiophene. According to Formula 1, Q may be phenyl, pyridine, pyrimidine or thiophene substituted with R 8 and R 9 . Although the positions of R 8 and R 9 in Q are not determined, they are positioned on different elements, and other positions may be bonded to hydrogen. Thus, when R 8 and R 9 are both hydrogen, it means that Q is unsubstituted phenyl, pyridine, pyrimidine or thiophene.
보다 바람직하게, 상기 화합물은More preferably, the compound
1) 2-(((3,3-디부틸-7-메틸티오-1,1-디옥시도-5-페닐-2,3,4,5-테트라하이드로벤조[b][1,4]티아제핀-8-일)메틸)아미노)아세트산;1) 2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo [b] [1,4] Thiazin-8-yl) methyl) amino) acetic acid;
2) 3-(((3,3-디부틸-7-메틸티오-1,1-디옥시도-5-페닐-2,3,4,5-테트라하이드로벤조[b][1,4]티아제핀-8-일)메틸)아미노)프로판산;2) 3-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo [b] [1,4] Thiazin-8-yl) methyl) amino) propanoic acid;
3) 2-(((3,3-디부틸-7-메틸티오-1,1-디옥시도-5-페닐-2,3,4,5-테트라하이드로벤조[b][1,4]티아제핀-8-일)메틸)아미노)숙신산;3) 2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo [b] [1,4] Thiazin-8-yl) methyl) amino) succinic acid;
4) (S)-2-(((3,3-디부틸-7-메틸티오-1,1-디옥시도-5-페닐-2,3,4,5-테트라하이드로벤조[b][1,4]티아제핀-8-일)메틸)아미노)프로판산;4) (S) -2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo [b] [ 1,4] thiazepin-8-yl) methyl) amino) propanoic acid;
5) 2-(((3,3-디부틸-7-메틸티오-1,1-디옥시도-5-페닐-2,3,4,5-테트라하이드로벤조[b][1,4]티아제핀-8-일)메틸)아미노)펜탄디오산;5) 2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo [b] [1,4] Thiazin-8-yl) methyl) amino) pentanedioic acid;
6) 4-아미노-2-(((3,3-디부틸-7-메틸티오-1,1-디옥시도-5-페닐-2,3,4,5-테트라하이드로벤조[b][1,4]티아제핀-8-일)메틸)아미노)-4-옥소부탄산;6) 4-amino-2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo [b] [ 1,4] thiazepin-8-yl) methyl) amino) -4-oxobutanoic acid;
7) (R)-2-(((3,3-디부틸-7-메틸티오-1,1-디옥시도-5-페닐-2,3,4,5-테트라하이드로벤조[b][1,4]티아제핀-8-일)메틸)아미노)프로판산;7) (R) -2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo [b] [ 1,4] thiazepin-8-yl) methyl) amino) propanoic acid;
8) 2-(((3,3-디부틸-7-메틸티오-1,1-디옥시도-5-페닐-2,3,4,5-테트라하이드로벤조[b][1,4]티아제핀-8-일)메틸)아미노)-2-메틸프로판산;8) 2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo [b] [1,4] Thiazin-8-yl) methyl) amino) -2-methylpropanoic acid;
9) (R)-2-(((3,3-디부틸-7-메틸티오-1,1-디옥시도-5-페닐-2,3,4,5-테트라하이드로벤조[b]1,4]티아제핀-8-일)메틸)아미노)-3-(1H-이미다졸-4-일)프로판산;9) (R) -2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo [b] 1 , 4] thiazepin-8-yl) methyl) amino) -3- (1H-imidazol-4-yl) propanoic acid;
10) (R)-2-(((3,3-디부틸-7-메틸티오-1,1-디옥시도-5-페닐-2,3,4,5-테트라하이드로벤조[b][1,4]티아제핀-8-일)메틸)아미노)-3-(1H-인돌-2-일)프로판산;10) (R) -2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo [b] [ 1,4] thiazepin-8-yl) methyl) amino) -3- (1H-indol-2-yl) propanoic acid;
11) (S)-2-(((3,3-디부틸-7-메틸티오-1,1-디옥시도-5-페닐-2,3,4,5-테트라하이드로벤조[b][1,4]티아제핀-8-일)메틸)아미노)-4-메틸펜탄산;11) (S) -2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo [b] [ 1,4] thiazepin-8-yl) methyl) amino) -4-methylpentanoic acid;
12) (S)-2-(((3,3-디부틸-7-메틸티오-1,1-디옥시도-5-페닐-2,3,4,5-테트라하이드로벤조[b][1,4]티아제핀-8-일)메틸)아미노)펜탄디오산;12) (S) -2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo [b] [ 1,4] thiazepin-8-yl) methyl) amino) pentanedioic acid;
13) (S)-2-(((3,3-디부틸-7-메틸티오-1,1-디옥시도-5-페닐-2,3,4,5-테트라하이드로벤조[b][1,4]티아제핀-8-일)메틸)아미노)-3-히드록시프로판산;13) (S) -2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo [b] [ 1,4] thiazepin-8-yl) methyl) amino) -3-hydroxypropanoic acid;
14) 3-((카복시메틸)((3,3-디부틸-7-메틸티오-1,1-디옥시도-5-페닐-2,3,4,5-테트라하이드로벤조[b][1,4]티아제핀-8-일)메틸)아미노)프로판산;14) 3-((carboxymethyl) ((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo [b] [ 1,4] thiazepin-8-yl) methyl) amino) propanoic acid;
15) 3-(((3,3-디부틸-7-메틸티오-1,1-디옥시도-5-페닐-2,3,4,5-테트라하이드로벤조[b][1,4]티아제핀-8-일)메틸)아미노)펜탄디오산;15) 3-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo [b] [1,4] Thiazin-8-yl) methyl) amino) pentanedioic acid;
16) 2-(((3,3-디부틸-7-메틸티오-1,1-디옥시도-5-페닐-2,3,4,5-테트라하이드로벤조[b][1,4]티아제핀-8-일)메틸)아미노)-2-옥소아세트산;16) 2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo [b] [1,4] Thiazin-8-yl) methyl) amino) -2-oxoacetic acid;
17) 1-(((3,3-디부틸-7-메틸티오-1,1-디옥시도-5-페닐-2,3,4,5-테트라하이드로벤조[b][1,4]티아제핀-8-일)메틸)아미노)사이클로프로판카복시산;17) 1-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo [b] [1,4] Thiazin-8-yl) methyl) amino) cyclopropanecarboxylic acid;
18) 2-(((3,3-디부틸-7-메틸티오-1,1-디옥시도-5-페닐-2,3,4,5-테트라하이드로벤조[b][1,4]티아제핀-8-일)메틸)아미노)-2-옥소에탄술폰산;18) 2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo [b] [1,4] Thiazin-8-yl) methyl) amino) -2-oxoethanesulfonic acid;
19) 2-(((3,3-디부틸-5-(4-메톡시페닐)-7-메틸티오-1,1-디옥시도-2,3,4,5-테트라하이드로벤조[b][1,4]티아제핀-8-일)메틸)아미노)아세트산;19) 2-(((3,3-dibutyl-5- (4-methoxyphenyl) -7-methylthio-1,1-dioxido-2,3,4,5-tetrahydrobenzo [b ] [1,4] thiazepin-8-yl) methyl) amino) acetic acid;
20) 2-(((3,3-디부틸-5-(4-히드록시페닐)-7-메틸티오-1,1-디옥시도-2,3,4,5-테트라하이드로벤조[b][1,4]티아제핀-8-일)메틸)아미노)아세트산;20) 2-(((3,3-dibutyl-5- (4-hydroxyphenyl) -7-methylthio-1,1-dioxido-2,3,4,5-tetrahydrobenzo [b ] [1,4] thiazepin-8-yl) methyl) amino) acetic acid;
21) 2-(((3,3-디부틸-5-(3-메톡시페닐)-7-메틸티오-1,1-디옥시도-2,3,4,5-테트라하이드로벤조[b][1,4]티아제핀-8-일)메틸)아미노)아세트산;21) 2-(((3,3-dibutyl-5- (3-methoxyphenyl) -7-methylthio-1,1-dioxido-2,3,4,5-tetrahydrobenzo [b ] [1,4] thiazepin-8-yl) methyl) amino) acetic acid;
22) 2-(((3,3-디부틸-5-(4-플루오로페닐)-7-메틸티오-1,1-디옥시도-2,3,4,5-테트라하이드로벤조[b][1,4]티아제핀-8-일)메틸)아미노)아세트산;22) 2-(((3,3-dibutyl-5- (4-fluorophenyl) -7-methylthio-1,1-dioxido-2,3,4,5-tetrahydrobenzo [b ] [1,4] thiazepin-8-yl) methyl) amino) acetic acid;
23) 2-(((3,3-디부틸-5-(3-플루오로페닐)-7-메틸티오-1,1-디옥시도-2,3,4,5-테트라하이드로벤조[b][1,4]티아제핀-8-일)메틸)아미노)아세트산;23) 2-(((3,3-dibutyl-5- (3-fluorophenyl) -7-methylthio-1,1-dioxido-2,3,4,5-tetrahydrobenzo [b ] [1,4] thiazepin-8-yl) methyl) amino) acetic acid;
24) 2-(((3,3-디부틸-5-(3-플루오로-4-메톡시페닐)-7-메틸티오-1,1-디옥시도-2,3,4,5-테트라하이드로벤조[b][1,4]티아제핀-8-일)메틸)아미노)아세트산;24) 2-(((3,3-dibutyl-5- (3-fluoro-4-methoxyphenyl) -7-methylthio-1,1-dioxido-2,3,4,5- Tetrahydrobenzo [b] [1,4] thiazepin-8-yl) methyl) amino) acetic acid;
25) 2-(((3,3-디부틸-5-(4-메톡시페닐)-7-메틸티오-1,1-디옥시도-2,3,4,5-테트라하이드로벤조[b][1,4]티아제핀-8-일)메틸)아미노)-2-옥소에탄술폰산;25) 2-(((3,3-dibutyl-5- (4-methoxyphenyl) -7-methylthio-1,1-dioxido-2,3,4,5-tetrahydrobenzo [b ] [1,4] thiazepin-8-yl) methyl) amino) -2-oxoethanesulfonic acid;
26) 1-(((3,3-디부틸-5-(3-플루오로-4-메톡시페닐)-7-메틸티오-1,1-디옥시도-2,3,4,5-테트라하이드로벤조[b][1,4]티아제핀-8-일)메틸)아미노)사이클로프로판카복시산;26) 1-(((3,3-dibutyl-5- (3-fluoro-4-methoxyphenyl) -7-methylthio-1,1-dioxido-2,3,4,5- Tetrahydrobenzo [b] [1,4] thiazepin-8-yl) methyl) amino) cyclopropanecarboxylic acid;
27) 2-(((3,3-디부틸-5-(4-플루오로페닐)-7-메틸티오-1,1-디옥시도-2,3,4,5-테트라하이드로벤조[b][1,4]티아제핀-8-일)메틸)아미노)-2-옥소아세트산;27) 2-(((3,3-dibutyl-5- (4-fluorophenyl) -7-methylthio-1,1-dioxido-2,3,4,5-tetrahydrobenzo [b ] [1,4] thiazepin-8-yl) methyl) amino) -2-oxoacetic acid;
28) (S)-2-(((3,3-디부틸-5-(4-플루오로페닐)-7-메틸티오-1,1-디옥시도-2,3,4,5-테트라하이드로벤조[b][1,4]티아제핀-8-일)메틸)아미노)프로판산;28) (S) -2-(((3,3-dibutyl-5- (4-fluorophenyl) -7-methylthio-1,1-dioxido-2,3,4,5-tetra Hydrobenzo [b] [1,4] thiazepin-8-yl) methyl) amino) propanoic acid;
29) (S)-2-(((3,3-디부틸-5-(4-플루오로페닐)-7-메틸티오-1,1-디옥시도-2,3,4,5-테트라하이드로벤조[b][1,4]티아제핀-8-일)메틸)아미노)-3-히드록시프로판산; 또는29) (S) -2-(((3,3-dibutyl-5- (4-fluorophenyl) -7-methylthio-1,1-dioxido-2,3,4,5-tetra Hydrobenzo [b] [1,4] thiazepin-8-yl) methyl) amino) -3-hydroxypropanoic acid; or
30) 1-(((3,3-디부틸-5-(4-플루오로페닐)-7-메틸티오-1,1-디옥시도-2,3,4,5-테트라하이드로벤조[b][1,4]티아제핀-8-일)메틸)아미노)사이클로프로판카복시산일 수 있다.30) 1-(((3,3-dibutyl-5- (4-fluorophenyl) -7-methylthio-1,1-dioxido-2,3,4,5-tetrahydrobenzo [b ] [1,4] thiazepin-8-yl) methyl) amino) cyclopropanecarboxylic acid.
또한, 본 발명의 화합물은 약학적으로 허용 가능한 염의 형태로 존재할 수 있다. 염으로는 약학적으로 허용가능한 유리산(free acid)에 의해 형성된 산가염이 유용하다. 본 발명의 용어 "약학적으로 허용가능한 염"이란 환자에게 비교적 비독성이고 무해한 유효작용을 갖는 농도로서 이 염에 기인한 부작용이 화학식 1로 표시되는 화합물의 이로운 효능을 저하시키지 않는 상기 화합물의 임의의 모든 유기 또는 무기 부가염을 의미한다.In addition, the compounds of the present invention may exist in the form of pharmaceutically acceptable salts. As salts are acid salts formed with pharmaceutically acceptable free acids. The term "pharmaceutically acceptable salt" of the present invention is any concentration of the compound which is relatively nontoxic to the patient and has a harmless effective action, in which the side effects caused by the salt do not degrade the beneficial efficacy of the compound represented by the formula (1). Means any organic or inorganic addition salt.
산부가염은 통상의 방법, 예를 들어 화합물을 과량의 산 수용액에 용해시키고, 이 염을 수혼화성 유기 용매, 예를 들어 메탄올, 에탄올, 아세톤 또는 아세토니트릴을 사용하여 침전시켜서 제조할 수 있다. 동 몰량의 화합물 및 물 중의 산 또는 알코올(예, 글리콜 모노메틸에테르)을 가열하고, 이어서 상기 혼합물을 증발시켜 건조시키거나, 또는 석출된 염을 흡인 여과시킬 수 있다.Acid addition salts can be prepared by conventional methods, for example by dissolving a compound in an excess of aqueous acid solution and precipitating the salt using a water miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. Equivalent molar amounts of the compound and acid or alcohol (eg, glycol monomethyl ether) in water can be heated and the mixture can then be evaporated to dryness or the precipitated salts can be suction filtered.
또한, 염기를 사용하여 약학적으로 허용가능한 금속염을 만들 수 있다. 알칼리 금속염 또는 알칼리 토금속염은, 예를 들어 화합물을 과량의 알칼리 금속 수산화물 또는 알칼리 토금속 수산화물 용액 중에 용해시키고, 비용해 화합물 염을 여과한 후 여액을 증발, 건조시켜 얻는다.Bases can also be used to make pharmaceutically acceptable metal salts. Alkali metal salts or alkaline earth metal salts are obtained, for example, by dissolving a compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and then evaporating and drying the filtrate.
본 발명의 화합물의 약학적으로 허용가능한 염은, 달리 지시되지 않는 한, 상기 화학식 1의 화합물에 존재할 수 있는 산성 또는 염기성 기의 염을 포함하며, 당업계에 알려진 염의 제조방법을 통하여 제조될 수 있다.Pharmaceutically acceptable salts of the compounds of the present invention, unless otherwise indicated, include salts of acidic or basic groups which may be present in the compound of Formula 1, and may be prepared through methods of preparing salts known in the art. have.
아울러, 본 발명의 화합물은 모핵 및 그 치환기에 비대칭 탄소중심을 가지므로 R 또는 S 이성질체, 라세미체, 부분입체이성질체 혼합물 및 개개 부분입체이성질체로서 존재할 수 있으며, 이들 모든 이성질체 및 이들의 혼합물은 본 발명의 범주에 포함된다.In addition, the compounds of the present invention have asymmetric carbon centers in the parent nucleus and its substituents and therefore may exist as R or S isomers, racemates, diastereomeric mixtures and individual diastereomers, all of these isomers and mixtures thereof. It is included in the scope of the invention.
예컨대, 본 발명의 화합물은 하기 반응식 1로 표시되는 일련의 반응을 통해 아미노-알콕시벤젠티올과 3-브로모-2-(모노 또는 디)알킬프로판산으로부터 합성될 수 있다. 그러나, 하기 반응식은 본 발명의 화합물의 예시적인 제조방법일 뿐, 본 발명의 화합물의 제조방법은 이에 제한되지 않으며, 당업게에 공지된 방법을 이용하거나 적절히 변경하여 수행될 수 있다.For example, the compounds of the present invention can be synthesized from amino-alkoxybenzenethiol and 3-bromo-2- (mono or di) alkylpropanoic acid through a series of reactions represented by Scheme 1 below. However, the following reaction scheme is merely an exemplary method for preparing the compound of the present invention, and the method for preparing the compound of the present invention is not limited thereto, and may be performed by using a method known in the art or by appropriately changing it.
[반응식 1]Scheme 1
Figure PCTKR2015009044-appb-I000003
Figure PCTKR2015009044-appb-I000003
상기 반응식에서 치환기는 앞서 정의한 바와 같다.The substituent in the above scheme is as defined above.
구체적으로, 단계 1은 화학식 2로 표시되는 화합물인 아미노-알콕시벤젠티올(예컨대, 아미노-메톡시벤젠티올)과 화학식 3으로 표시되는 3-브로모-2-(모노 또는 디)알킬프로판산 유도체(예컨대, 3-브로모-2,2-디부틸프로판산 a.k.a. 2-브로모메틸-2-부틸헥산산)를 반응시켜 화학식 4로 표시되는 화합물을 제조하는 단계로, 바람직하게, 상기 단계 1의 반응은 수산화칼륨 존재하에 수행할 수 있으며, 용매로는 물을 사용할 수 있으나, 이에 제한되지 않는다.Specifically, step 1 is an amino-alkoxybenzenethiol (eg, amino-methoxybenzenethiol) which is a compound represented by the formula (2) and 3-bromo-2- (mono or di) alkylpropanoic acid derivative represented by the formula (3). Reacting (for example, 3-bromo-2,2-dibutylpropanoic acid aka 2-bromomethyl-2-butylhexanoic acid) to prepare a compound represented by Chemical Formula 4, preferably, Step 1 The reaction of may be carried out in the presence of potassium hydroxide, water may be used as a solvent, but is not limited thereto.
단계 2는 벤조티아제핀를 형성하기 위한 고리화 반응으로서, 상기 단계 1로부터 제조된 화학식 4로 표시되는 화합물을 HATU(1-[비스(디메틸아미노)메틸렌]-1H-1,2,3-트리아졸로[4,5-b]피리디늄 3-옥시드 헥사플루오로포스페이트)와 반응시켜 화학식 5로 표시되는 3,3-디알킬-8-알콕시-2,3-디하이드로벤조[b][1,4]티아제핀-4(5H)-온 유도체를 제조하는 단계이다. 바람직하게, 상기 단계 2의 용매로는 디클로로메탄을 사용할 수 있으나, 이에 제한되지 않는다.Step 2 is a cyclization reaction for forming benzothiazepine, wherein the compound represented by Formula 4 prepared in Step 1 is prepared by HATU (1- [bis (dimethylamino) methylene] -1H-1,2,3-tria 3,3-dialkyl-8-alkoxy-2,3-dihydrobenzo [b] [1 represented by the formula (5) by reacting with zolo [4,5-b] pyridinium 3-oxide hexafluorophosphate) , 4] thiazepin-4 (5H) -one derivative. Preferably, dichloromethane may be used as the solvent of step 2, but is not limited thereto.
단계 3은 반응성 치환기로서 브로모기를 도입하는 단계로서, 상기 단계 2로부터 제조된 화학식 5로 표시되는 화합물과 N-브로모숙신이미드를 반응시켜 화학식 6으로 표시되는 7-브로모-3,3-디알킬-8-알콕시-2,3-디하이드로벤조[b][1,4]티아제핀-4(5H)-온 유도체를 제조하는 단계이다. 바람직하게, 상기 단계 3의 용매로는 디클로로메탄을 사용할 수 있으나, 이에 제한되지 않는다. 상기 N-브로모숙신이미드 대신에 다른 할로겐 원소를 포함하는 N-할로숙신이미드를 사용할 수 있다. 상기 살로겐 원소로는 이후 치환반응에서 충분한 반응성을 나타낼 수 있는 치환기를 제공할 수 있는 것이면 제한없이 사용할 수 있다.Step 3 is a step of introducing a bromo group as a reactive substituent, 7-bromo-3,3 represented by the formula (6) by reacting the compound represented by the formula (5) prepared in step 2 with N-bromosuccinimide -Dialkyl-8-alkoxy-2,3-dihydrobenzo [b] [1,4] thiazepin-4 (5H) -one derivative. Preferably, dichloromethane may be used as the solvent of step 3, but is not limited thereto. Instead of the N-bromosuccinimide, N-halosuccinimide containing another halogen element can be used. The salogen element may be used without limitation as long as it can provide a substituent capable of exhibiting sufficient reactivity in the subsequent substitution reaction.
단계 4는 티아제핀 고리의 질소원자 상에 치환기를 도입하는 단계로서, 상기 단계 3으로부터 제조된 화학식 6으로 표시되는 화합물과 화학식 7로 표시되는 요오드화 화합물과 반응시킴으로서 달성할 수 있다. 바람직하게, 상기 단계 4의 반응은 CuI 존재하에 수행할 수 있으며, 용매로는 자일렌(xylene)을 사용할 수 있으나, 이에 제한되지 않는다.Step 4 is a step of introducing a substituent on the nitrogen atom of the thiazepine ring, it can be achieved by reacting the compound represented by the formula (6) prepared from step 3 with the iodide compound represented by the formula (7). Preferably, the reaction of step 4 may be carried out in the presence of CuI, xylene may be used as the solvent, but is not limited thereto.
단계 5는 환원반응에 의해 티아제핀 고리 상의 케톤기를 제거하는 단계로서, 환원제로는 LiAlH4를 사용할 수 있으나, 이에 제한되는 것은 아니며, 티아제핀 고리 상의 케톤기를 선택적으로 환원시켜 -(C=O)-기를 -CH2-로 변환시킬 수 있는 환원제를 제한없이 사용할 수 있다. 바람직하게, 상기 단계 5의 용매로는 디에틸에테르를 사용할 수 있으나, 이에 제한되지 않는다.Step 5 is a step of removing the ketone group on the tiazine ring by a reduction reaction, LiAlH 4 may be used as the reducing agent, but is not limited thereto. The ketone group on the tiazine ring may be selectively reduced to reduce-(C = O). Reducing agents capable of converting -groups to -CH 2 -can be used without limitation. Preferably, diethyl ether may be used as the solvent of step 5, but is not limited thereto.
단계 6은 오스뮴테트록사이드로 산화시켜 티아제핀의 디옥사이드 유도체를 제조하는 단계로서, 바람직하게, 상기 단계 6의 용매로는 테트라하이드로퓨란과 t-부탄올의 혼합 용매를 사용할 수 있으나, 이에 제한되지 않는다.Step 6 is a step of preparing a dioxide derivative of thiazepine by oxidizing with osmium tetroxide. Preferably, a mixed solvent of tetrahydrofuran and t-butanol may be used as the solvent of step 6, but is not limited thereto. .
단계 7은 치환반응에 의해 반응성 할로겐이 치환된 자리에 치환기 R5를 도입하는 동시에 벤조 고리 상의 알콕시기를 히드록시기로 변환시키는 단계로서, 치환반응을 위한 반응물로는 도입하고자 하는 치환기의 금속염, 예컨대, 알칼리금속염(M-R5; M은 알칼리금속)을 사용할 수 있다. 바람직하게, 상기 단계 7의 용매로는 디메틸포름아미드(DMF)를 사용할 수 있으나, 이에 제한되지 않는다.Step 7 is a step of introducing a substituent R 5 at a position where a reactive halogen is substituted by a substitution reaction, and simultaneously converting an alkoxy group on a benzo ring to a hydroxyl group. As a reactant for the substitution reaction, a metal salt of a substituent to be introduced, such as an alkali, is introduced. Metal salts (MR 5 ; M is an alkali metal) can be used. Preferably, dimethylformamide (DMF) may be used as the solvent of step 7, but is not limited thereto.
단계 8은 벤조 고리 상의 히드록시기를 우수한 이탈기(good leaving group)인 트리플루오로메탄설포네이트(a.k.a. 트리플레이트; OTf)로 변환하는 단계로서, OTf 도입을 위한 반응물로는 트리플로오로메탄설포닉 언하이드라이드(TfO2)를 사용할 수 있다. 바람직하게, 상기 단계 8의 용매로는 디클로로메탄을 사용할 수 있으나, 이에 제한되지 않는다.Step 8 converts the hydroxy group on the benzo ring to trifluoromethanesulfonate (aka triflate; OTf), which is a good leaving group. The reactant for introducing OTf is trifluoromethanesulphonic Hydride (TfO 2 ) can be used. Preferably, dichloromethane may be used as the solvent of step 8, but is not limited thereto.
단계 9는 아미노메틸기의 전구체로서 시아노기를 도입하는 단계로서, 상기 제8단계로부터 제조된 OTf기가 도입된 화합식 13으로 표시되는 화합물을 시안화 아연과 반응시킴으로써 OTf기를 CN기로 치환하는 단계이다. 바람직하게, 상기 단계 1의 반응은 팔라듐 존재하에 수행할 수 있으며, 용매로는 디메틸포름아미드를 사용할 수 있으나, 이에 제한되지 않는다.Step 9 is a step of introducing a cyano group as a precursor of the aminomethyl group, the step of replacing the OTf group with a CN group by reacting the compound represented by the formula (13) to which the OTf group prepared from the above step 8 is introduced with zinc cyanide. Preferably, the reaction of Step 1 may be carried out in the presence of palladium, dimethylformamide may be used as the solvent, but is not limited thereto.
단계 10은 상기 단계 9를 통해 시아노기를 도입한 화합물을 디이소부틸알루미늄 하이드라이드(DIBAL-H)와 반응시켜 상기 시아노기를 포르밀기로 변환시키는 단계이다. 바람직하게, 상기 단계 10의 용매로는 디클로로메탄을 사용할 수 있으나, 이에 제한되지 않는다.Step 10 is a step of converting the cyano group to formyl by reacting a compound introduced with a cyano group through step 9 with diisobutylaluminum hydride (DIBAL-H). Preferably, dichloromethane may be used as the solvent of step 10, but is not limited thereto.
단계 11은 상기 단계 10으로부터 제조된 화학식 15로 표시되는 화합물을 아민 유도체와 축합반응시켜 표제 화합물을 수득하는 단계이다. 바람직하게, 상기 단계 11의 반응은 소듐 트리아세톡시보로하이드라이드(NaB(OAc)3H) 존재하에 수행할 수 있으며, 용매로는 디클로로에탄을 사용할 수 있으나, 이에 제한되지 않는다.Step 11 is a step of condensing the compound represented by Formula 15 prepared in Step 10 with an amine derivative to obtain the title compound. Preferably, the reaction of step 11 may be carried out in the presence of sodium triacetoxyborohydride (NaB (OAc) 3 H), dichloroethane may be used as a solvent, but is not limited thereto.
다른 하나의 양태로서, 본 발명은 상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 변비의 예방 또는 치료용 약학적 조성물을 제공한다.As another aspect, the present invention provides a pharmaceutical composition for the prevention or treatment of constipation comprising the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명에서 사용되는 용어, "예방"은 상기 약학적 조성물의 투여로 변비의 발생, 확산 및 재발을 억제시키거나 지연시키는 모든 행위를 의미하고, "치료"는 상기 약학적 조성물의 투여로 상기 질환의 증세가 호전되거나 이롭게 변경되는 모든 행위를 의미한다.As used herein, the term "prevention" means any action that inhibits or delays the occurrence, spread and recurrence of constipation by administration of the pharmaceutical composition, and "treatment" refers to the disease by administration of the pharmaceutical composition. Means any action that improves or beneficially changes the condition of
본 발명에 따른 약학적 조성물은 유효성분으로서 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을 함유할 수 있고, 또한 약학적으로 허용 가능한 담체, 희석제 또는 부형제를 추가로 포함할 수 있다.The pharmaceutical composition according to the present invention may contain the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient, and may further include a pharmaceutically acceptable carrier, diluent or excipient.
본 발명의 조성물은 약학적으로 유효한 양으로 투여한다. 본 발명의 용어 "약학적으로 유효한 양"은 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분하며 부작용을 일으키지 않을 정도의 양을 의미하며, 본 발명의 용어 "투여"는 임의의 적절한 방법으로 환자에게 소정의 물질을 제공하는 것을 의미한다.The composition of the present invention is administered in a pharmaceutically effective amount. The term "pharmaceutically effective amount" of the present invention means an amount sufficient to treat the disease at a reasonable benefit / risk ratio applicable to the medical treatment and not causing side effects, and the term "administration" of the present invention may be any Means providing the patient with the desired material in an appropriate manner.
본 발명에서 유효성분과 결합하여 사용된 "치료학적으로 유효한 양"이란 용어는 대상 질환을 예방 또는 치료하는데 유효한 아미노알킬벤조티아제핀 유도체 화합물 또는 이의 약학적으로 허용가능한 염의 양을 의미한다.The term "therapeutically effective amount" as used in combination with an active ingredient in the present invention means an amount of an aminoalkylbenzothiazepine derivative compound or a pharmaceutically acceptable salt thereof effective for preventing or treating a subject disease.
본 발명의 약학적 조성물은 예방 또는 치료하고자 하는 질환의 종류에 따라, 유효성분으로서 아미노알킬벤조티아제핀 유도체 화합물 또는 이의 약학적으로 허용가능한 염 이외의 각 질환의 예방 또는 치료에 사용되는 공지의 약물을 추가로 포함할 수 있다.The pharmaceutical composition of the present invention is a known drug used for the prevention or treatment of each disease other than an aminoalkylbenzothiazepine derivative compound or a pharmaceutically acceptable salt thereof as an active ingredient, depending on the type of disease to be prevented or treated. It may further include.
이하, 본 발명의 이해를 돕기 위하여 바람직한 실시예를 제시한다. 그러나 하기의 실시예는 본 발명을 더욱 쉽게 이해하기 위하여 제공되는 것일 뿐, 실시예에 의하여 본 발명의 내용이 한정되는 것은 아니다.Hereinafter, preferred examples are provided to aid in understanding the present invention. However, the following examples are merely provided to more easily understand the present invention, and the contents of the present invention are not limited by the examples.
본 발명의 화합물을 합성하기 위한 출발 물질의 다양한 합성법이 알려져 있으며, 상기 출발 물질이 시판되고 있는 경우는 공급처로부터 구매하여 사용할 수 있다. 시약 공급처로는 Sigma-Aldrich, TCI, Wako, Kanto, Fluorchem, Acros, Alfa, Fluka, Dae-Jung 등의 회사가 있으나 이에 한정되는 것은 아니다. 또한, 다른 식으로 규정되는 경우를 제외하고 시판된 모든 물질은 추가적으로 정제하지 않고 사용하였다.Various synthesis methods of starting materials for synthesizing the compounds of the present invention are known, and if the starting materials are commercially available, they can be purchased from a supplier and used. Reagent suppliers include, but are not limited to, companies such as Sigma-Aldrich, TCI, Wako, Kanto, Fluorchem, Acros, Alfa, Fluka, Dae-Jung, and the like. In addition, all commercially available materials were used without further purification except as otherwise defined.
먼저, 이하 실시예에서 합성에 사용되는 화합물을 하기 제조예와 같이 제조하였다. 이하의 제조예들은 앞서 반응식 1의 예이며, 제조하고자 하는 실시예의 구조에 상응하여 적절히 변경할 수 있다.First, the compounds used for synthesis in the following Examples were prepared as in the following Preparation Examples. The following preparation examples are examples of Scheme 1 above, and may be appropriately changed according to the structure of the embodiment to be prepared.
제조예Production Example 1: 31: 3 ,3-, 3- 디부틸Dibutyl -7--7- 메틸티오Methylthio -5-페닐-2,3,4,5--5-phenyl-2,3,4,5- 테트라하이드로벤조[b][1,4]티아제핀Tetrahydrobenzo [b] [1,4] thiazepine -8-카브알데하이드 1,1-디옥사이드의 제조Preparation of -8-carbaldehyde 1,1-dioxide
단계 1) 2-(((2-아미노-5-메톡시페닐)티오)메틸)-2-부틸헥사노익산의 제조Step 1) Preparation of 2-(((2-amino-5-methoxyphenyl) thio) methyl) -2-butylhexanoic acid
Figure PCTKR2015009044-appb-I000004
Figure PCTKR2015009044-appb-I000004
30% 수산화칼륨 250 ㎖에 6-메톡시벤조[d]티아졸-2-아민(25 g, 139.7 mmol)을 넣고 온도 140℃에서 18시간 동안 교반하였다. 반응액을 TLC로 체크하여 2-아미노-5-메톡시벤젠티올의 형성을 확인한 후 반응액을 상온으로 냉각하였다. 이후 2-브로모메틸-2-부틸헥산산(44.6 g, 167.7 mmol)을 첨가하고 상온에서 약 17시간 동안 교반하였다. 염화암모늄 포화용액과 디클로로메탄을 첨가하고 10분 동안 교반한 뒤 디클로로메탄층을 추출하는 과정을 3회 반복하였다. 디클로로메탄층에 무수 황산마그네슘을 넣고 여과한 뒤 농축하였다. 수득한 농축 화합물에 t-부틸 메틸 에테르와 6N 염산 용액을 첨가하여 에테르층을 추출하고 다시 농축하였다. 농축한 화합물은 갈색 고체이며, 여기에 헥산을 첨가하고 교반한 후 여과하여 51%의 수율로 아이보리색 고체 25 g을 수득하였다.6-methoxybenzo [d] thiazol-2-amine (25 g, 139.7 mmol) was added to 250 mL of 30% potassium hydroxide and stirred at 140 ° C. for 18 hours. After checking the reaction solution by TLC to confirm the formation of 2-amino-5-methoxybenzenethiol, the reaction solution was cooled to room temperature. Then 2-bromomethyl-2-butylhexanoic acid (44.6 g, 167.7 mmol) was added and stirred at room temperature for about 17 hours. After adding saturated ammonium chloride solution and dichloromethane and stirring for 10 minutes, the process of extracting the dichloromethane layer was repeated three times. Anhydrous magnesium sulfate was added to the dichloromethane layer, filtered, and concentrated. To the concentrated compound obtained was added t-butyl methyl ether and 6N hydrochloric acid solution to extract the ether layer and concentrated again. The concentrated compound is a brown solid, to which hexane is added, stirred and filtered to give 25 g of ivory solid in 51% yield.
단계 2) 7-Step 2) 7- 브로모Bromo -3,3--3,3- 디부틸Dibutyl -8--8- 메톡시Methoxy -2,3--2,3- 디하이드로벤조[b][1,4]티아제핀Dihydrobenzo [b] [1,4] thiazepine -4(5H)-온의 제조Preparation of -4 (5H) -one
Figure PCTKR2015009044-appb-I000005
Figure PCTKR2015009044-appb-I000005
상기 단계 1)로부터 수득한 2-(((2-아미노-5-메톡시페닐)티오)메틸)-2-부틸헥사노익산(25 g, 71.78 mmol)을 디클로로메탄 900 ㎖에 넣고 -40℃로 냉각시켰다. 온도가 -40℃까지 떨어지면 1-[비스(디메틸아미노)메틸렌]-1H-1,2,3-트리아졸로[4,5-b]피리디늄 3-옥시드 헥사플루오로포스페이트(41 g, 107.68 mmol; HATU)를 천천히 나누어 첨가하고 약 10분 동안 교반하였다. 이후 디이소프로필아민 58.15 ㎖(358.9 mmol)을 천천히 적가하였다. 디이소프로필아민의 첨가가 완료된 시점으로부터 약 5시간 동안 교반하였다. 염화암모늄 포화용액을 첨가한 뒤 디클로로메탄층을 추출하는 과정을 3번 반복하였다. 추출한 디클로로메탄층에 무수 황산마그네슘을 넣고 여과한 뒤 농축시켜 3,3-디부틸-8-메톡시-2,3-디하이드로벤조[b][1,4]티아제핀-4(5H)-온 23 g을 수득하였다. 상기 화합물에 디클로로메탄 480 ㎖를 가하고 0℃로 냉각시켰다. 온도를 낮춘 다음 N-브로모숙신이미드 14.51 g(81.54 mmol)을 천천히 첨가하고, 약 4시간 동안 교반하였다. 염화암모늄 포화용액을 첨가하고 디클로로메탄층을 추출하였다. 추출한 디클로로메탄층에 무수 황산마그네슘을 넣고 여과한 뒤 농축하였다. 농축한 화합물에 헥산 : 에틸아세테이트 = 30 : 1 용액 200 ㎖를 가하고 교반하면서 헥산 200 ㎖를 더 추가하여 생긴 고체를 여과하여 50%의 수율로 표제화합물 7-브로모-3,3-디부틸-8-메톡시-2,3-디하이드로벤조[b][1,4]티아제핀-4(5H)-온 14 g을 수득하였다.2-(((2-amino-5-methoxyphenyl) thio) methyl) -2-butylhexanoic acid (25 g, 71.78 mmol) obtained in step 1) was added to 900 mL of dichloromethane and then -40 ° C. Cooled to. When the temperature drops to -40 ° C, 1- [bis (dimethylamino) methylene] -1H-1,2,3-triazolo [4,5-b] pyridinium 3-oxide hexafluorophosphate (41 g, 107.68) mmol; HATU) was slowly added in portions and stirred for about 10 minutes. 58.15 mL (358.9 mmol) of diisopropylamine was then slowly added dropwise. The mixture was stirred for about 5 hours from when the addition of diisopropylamine was completed. After adding saturated ammonium chloride solution, the process of extracting the dichloromethane layer was repeated three times. Anhydrous magnesium sulfate was added to the extracted dichloromethane layer, filtered, and concentrated to give 3,3-dibutyl-8-methoxy-2,3-dihydrobenzo [b] [1,4] thiazepine-4 (5H)- 23 g was obtained. 480 mL of dichloromethane was added to the compound and cooled to 0 ° C. After the temperature was lowered, 14.51 g (81.54 mmol) of N-bromosuccinimide was slowly added and stirred for about 4 hours. A saturated ammonium chloride solution was added and the dichloromethane layer was extracted. Anhydrous magnesium sulfate was added to the extracted dichloromethane layer, and the filtrate was concentrated. To the concentrated compound, 200 ml of hexane: ethyl acetate = 30: 1 solution was added, and 200 ml of hexane was further added while stirring, and the solid formed was filtered to give the title compound 7-bromo-3,3-dibutyl- in a yield of 50%. 14 g of 8-methoxy-2,3-dihydrobenzo [b] [1,4] thiazepin-4 (5H) -one were obtained.
1H NMR (400 MHz, CDCl3) δ 7.58 (s, 1H), 6.99 (d, J = 2.8 Hz, 1H), 6.87 (d, J = 8.8 Hz, 1H), 6.77 (dd, J = 8.8 Hz, 2.8 Hz, 1H), 3.78 (s, 3H), 2.97 (s, 2H), 1.78-1.85 (m, 2H), 1.55-1.62 (m, 2H), 1.18-1.30 (m, 8H), 0.87 (t, J = 6.8 Hz, 6H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.58 (s, 1H), 6.99 (d, J = 2.8 Hz, 1H), 6.87 (d, J = 8.8 Hz, 1H), 6.77 (dd, J = 8.8 Hz , 2.8 Hz, 1H), 3.78 (s, 3H), 2.97 (s, 2H), 1.78-1.85 (m, 2H), 1.55-1.62 (m, 2H), 1.18-1.30 (m, 8H), 0.87 ( t, J = 6.8 Hz, 6H).
단계 3) 3,3-Step 3) 3,3- 디부틸Dibutyl -8-히드록시-7--8-hydroxy-7- 메틸티오Methylthio -5-페닐-2,3,4,5--5-phenyl-2,3,4,5- 테트라하이드로벤조[b][1,4]티아제핀Tetrahydrobenzo [b] [1,4] thiazepine 디옥사이드의Dioxide 제조 Produce
Figure PCTKR2015009044-appb-I000006
Figure PCTKR2015009044-appb-I000006
상기 단계 2)로부터 수득한 7-브로모-3,3-디부틸-8-메톡시-2,3-디하이드로벤조[b][1,4]티아제핀-4(5H)-온 5.77 g(14.44 mmol)에 요오드화 벤젠 50 ㎖, 요오드화 구리 0.55 g(2.89 mmol), 탄산칼륨 4g(28.9 mmol), 트리스[2-(2-메톡시에톡시)에틸]아민 0.5 ㎖ (1.44 mmol)을 넣고 상온에서 약 5분 동안 교반한 뒤 190℃에서 17시간 동안 환류시켰다. 상온으로 식힌 뒤 실리카 여과하고 헥산으로 세척하여 요오드화 벤젠을 제거한 뒤 실리카에 포획된 화합물을 에틸아세테이트와 디클로로메탄으로 용출시켜 회수한 용액을 농축시켜 7-브로모-3,3-디부틸-8-메톡시-5-페닐-2,3-디하이드로벤조[b][1,4]티아제핀-4(5H)-온을 5.8g 수득하였다. 리튬알루미늄하이드라이드 1.4 g(36.88 mmol)을 500 ㎖ 둥근 바닥 플라스크에 넣어 진공건조시켰다. 디에틸에테르 150 ㎖를 가하고 -10℃로 냉각시킨 후 무수 황산 1 ㎖(18.44 mmol)을 천천히 적가하였다. 상기 수득한 7-브로모-3,3-디부틸-8-메톡시-5-페닐-2,3-디하이드로벤조[b][1,4]티아제핀-4(5H)-온을 디에틸에테르에 녹여 반응 플라스크에 적가하였다. 상온에서 2시간 동안 교반한 뒤 염화암모늄 포화용액을 넣고 디에틸에테르층을 추출하였다. 무수 황산마그네슘을 넣고 여과한 후 농축하여 7-브로모-3,3-디부틸-8-메톡시-5-페닐-2,3,4,5-테트라하이드로벤조[b][1,4]티아제핀 5 g을 수득하였다. 수득한 화합물 5g (10.98 mmol)에 테트라하이드로퓨란 : t-부탄올 = 1 : 1 75 ㎖, 오스뮴테트록사이드 0.07 g(0.27 mmol), N-메틸몰포린 N-옥사이드 3.96 g(32.94 mmol)을 넣고 상온에서 12시간 동안 교반하였다. 염화암모늄 포화용액과 디클로로메탄을 넣고 디클로로메탄층을 추출한 뒤 농축하여 3.55 g의 7-브로모-3,3-디부틸-8-메톡시-5-페닐-2,3,4,5-테트라하이드로벤조[b][1,4]티아제핀 디옥사이드 화합물을 아이보리색 고체로 수득하였다. 수득한 화합물 3.55 g(7.18 mmol) 에 디메틸포름아미드 100 ㎖, 소듐티오메톡사이드 5.032 g(71.79 mmol), 소듐보로하이드라이드 5.43 g(143.6 mmol)을 넣고 60℃에서 15시간 동안 교반하였다. 염화암모늄 포화용액과 t-부틸메틸에테르를 넣고 에테르층을 추출한 뒤 농축하였다. 농축한 화합물에 헥산을 가하고 고체를 여과하여 84%의 수율로 3,3-디부틸-8-히드록시-7-메틸티오-5-페닐-2,3,4,5-테트라하이드로벤조[b][1,4]티아제핀 디옥사이드 2.7 g을 수득하였다.5.77 g of 7-bromo-3,3-dibutyl-8-methoxy-2,3-dihydrobenzo [b] [1,4] thiazepin-4 (5H) -one obtained from step 2) above 50 mL of benzene iodide, 0.55 g (2.89 mmol) of copper iodide, 4 g (28.9 mmol) of potassium carbonate, and 0.5 mL (1.44 mmol) of tris [2- (2-methoxyethoxy) ethyl] amine were added to (14.44 mmol). After stirring for about 5 minutes at room temperature it was refluxed at 190 ℃ for 17 hours. After cooling to room temperature, silica filtered and washed with hexane to remove benzene iodide, the compound captured in silica was eluted with ethyl acetate and dichloromethane, and the recovered solution was concentrated to 7-bromo-3,3-dibutyl-8-. 5.8 g of methoxy-5-phenyl-2,3-dihydrobenzo [b] [1,4] thiazepin-4 (5H) -one were obtained. 1.4 g (36.88 mmol) of lithium aluminum hydride was put into a 500 mL round bottom flask and dried in vacuo. 150 ml of diethyl ether was added, cooled to -10 deg. C, and 1 ml (18.44 mmol) of sulfuric anhydride was slowly added dropwise. Obtained 7-bromo-3,3-dibutyl-8-methoxy-5-phenyl-2,3-dihydrobenzo [b] [1,4] thiazepin-4 (5H) -one as obtained above. It was dissolved in ethyl ether and added dropwise to the reaction flask. After stirring for 2 hours at room temperature, saturated ammonium chloride solution was added thereto, and the diethyl ether layer was extracted. Anhydrous magnesium sulfate was added, filtered and concentrated to 7-bromo-3,3-dibutyl-8-methoxy-5-phenyl-2,3,4,5-tetrahydrobenzo [b] [1,4] 5 g of tiazine was obtained. To 5 g (10.98 mmol) of the obtained compound, tetrahydrofuran: t-butanol = 1: 1 75 ml, 0.07 g (0.27 mmol) of osmium tetraoxide, and 3.96 g (32.94 mmol) of N-methylmorpholine N-oxide were added thereto. Stir at room temperature for 12 hours. Saturated ammonium chloride solution and dichloromethane were added, the dichloromethane layer was extracted, concentrated, and 3.55 g of 7-bromo-3,3-dibutyl-8-methoxy-5-phenyl-2,3,4,5-tetra Hydrobenzo [b] [1,4] thiazepine dioxide compound was obtained as an ivory solid. To 3.55 g (7.18 mmol) of the obtained compound, 100 ml of dimethylformamide, 5.032 g (71.79 mmol) of sodium thiomethoxide, and 5.43 g (143.6 mmol) of sodium borohydride were added thereto and stirred at 60 ° C. for 15 hours. A saturated ammonium chloride solution and t-butyl methyl ether were added thereto, the ether layer was extracted and concentrated. Hexane was added to the concentrated compound, and the solid was filtered to give 3,3-dibutyl-8-hydroxy-7-methylthio-5-phenyl-2,3,4,5-tetrahydrobenzo [b in 84% yield. ] 2.7 g of [1,4] thiazepine dioxide were obtained.
1H NMR (400 MHz, CDCl3) δ 7.31 (s, 1H), 7.16 (t, J = 8 Hz, 2H), 6.92 (d, J = 8 Hz, 2H), 6.84 (t, J = 6.8 Hz, 1H), 6.67 (s, 1H), 3.61 (s, 2H), 3.07 (s, 2H), 2.15 (s, 3H), 1.28-1.44 (m, 4H), 1.97-1.19 (m, 8H), 0.74 (t, J = 6.8 Hz). 1 H NMR (400 MHz, CDCl 3 ) δ 7.31 (s, 1H), 7.16 (t, J = 8 Hz, 2H), 6.92 (d, J = 8 Hz, 2H), 6.84 (t, J = 6.8 Hz , 1H), 6.67 (s, 1H), 3.61 (s, 2H), 3.07 (s, 2H), 2.15 (s, 3H), 1.28-1.44 (m, 4H), 1.97-1.19 (m, 8H), 0.74 (t, J = 6.8 Hz).
단계 4) 3,3-Step 4) 3,3- 디부틸Dibutyl -7--7- 메틸티오Methylthio -1,1--1,1- 디옥사이도Dioxado -5-페닐-2,3,4,5--5-phenyl-2,3,4,5- 테트라하이드로벤조[b][1,4]티아제핀Tetrahydrobenzo [b] [1,4] thiazepine -8-일 트리플루오로메탄설포네이트의 제조Preparation of -8-yl Trifluoromethanesulfonate
Figure PCTKR2015009044-appb-I000007
Figure PCTKR2015009044-appb-I000007
상기 단계 3)으로부터 수득한 3,3-디부틸-8-히드록시-7-메틸티오-5-페닐-2,3,4,5-테트라하이드로벤조[b][1,4]티아제핀 디옥사이드 2.7 g(5.98 mmol)에 디클로로메탄 30 ㎖, 피리딘 0.63 ㎖(7.77 mmol)을 첨가한 후 0℃로 냉각시켰다. 트리플로오로메탄설포닉 언하이드라이드 1.3 ㎖(7.77 mmol)을 천천히 적가한 뒤 상온에서 5시간 동안 교반하였다. 염화암모늄 포화용액을 넣고 디클로로메탄층을 추출한 뒤 무수 황산마그네슘을 넣고 여과시켜 농축하였다. 실리카 컬럼크로마토그래피를 이용하여 헥산 : 에틸아세테이트 = 8 : 1 비율의 혼합 용매로 정제하였다. 그 결과 86%의 수율로 3,3-디부틸-7-메틸티오-1,1-디옥사이도-5-페닐-2,3,4,5-테트라하이드로벤조[b][1,4]티아제핀-8-일 트리플루오로메탄설포네이트 2.96 g을 수득하였다.3,3-dibutyl-8-hydroxy-7-methylthio-5-phenyl-2,3,4,5-tetrahydrobenzo [b] [1,4] thiazepine dioxide obtained from step 3) above To 2.7 g (5.98 mmol) was added 30 ml of dichloromethane and 0.63 ml (7.77 mmol) of pyridine, followed by cooling to 0 ° C. 1.3 ml (7.77 mmol) of trifluoromethanesulphonic anhydride was slowly added dropwise and stirred at room temperature for 5 hours. A saturated ammonium chloride solution was added thereto, the dichloromethane layer was extracted, anhydrous magnesium sulfate was added thereto, and the filtrate was concentrated. Purification was carried out using silica column chromatography with a mixed solvent of hexane: ethyl acetate = 8: 1 ratio. The result is 3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo [b] [1,4] with a yield of 86%. 2.96 g of thiazin-8-yl trifluoromethanesulfonate was obtained.
1H NMR (400 MHz, CDCl3) δ 7.81 (s, 1H), 7.39 (t, J = 7.6 Hz, 2H), 7.21 (d, J = 7.6 Hz, 2H), 7.18 (d, J = 7.2 Hz, 1H), 6.46 (s, 1H), 3.89 (s, 2H), 3.26 (s, 2H), 2.13 (s, 3H), 1.48-1.85 (m, 2H), 1.35-1.42 (m, 2H), 1.01-1.20 (m, 8H), 0.74 (t, J = 6.8 Hz). 1 H NMR (400 MHz, CDCl 3 ) δ 7.81 (s, 1H), 7.39 (t, J = 7.6 Hz, 2H), 7.21 (d, J = 7.6 Hz, 2H), 7.18 (d, J = 7.2 Hz , 1H), 6.46 (s, 1H), 3.89 (s, 2H), 3.26 (s, 2H), 2.13 (s, 3H), 1.48-1.85 (m, 2H), 1.35-1.42 (m, 2H), 1.01-1.20 (m, 8 H), 0.74 (t, J = 6.8 Hz).
단계 5) 3,3-Step 5) 3,3- 디부틸Dibutyl -7--7- 메틸티오Methylthio -5-페닐-2,3,4,5--5-phenyl-2,3,4,5- 테트라하이드로벤조[b][1,4]티아제핀Tetrahydrobenzo [b] [1,4] thiazepine -8-카보니트릴 디옥사이드의 제조Preparation of -8-carbonitrile dioxide
Figure PCTKR2015009044-appb-I000008
Figure PCTKR2015009044-appb-I000008
상기 단계 4)로부터 수득한 3,3-디부틸-7-메틸티오-1,1-디옥사이도-5-페닐-2,3,4,5-테트라하이드로벤조[b][1,4]티아제핀-8-일 트리플루오로메탄설포네이트 2.96 g(5.12 mmol)에 디메틸포름아미드 60 ㎖, 아연 분말 0.034 g(0.512 mmol), 시안화 아연 0.66 g(5.632 mmol), 트리스(디벤질리덴아세톤)디팔라듐 0.47 g(0.51 mmol), 1,1-비스(디페닐포스피노)페로센 0.34 g(0.614 mmol)을 넣고 80℃에서 20시간 동안 교반하였다. 상온으로 냉각시킨 뒤 염화암모늄 포화용액, 에틸아세테이트를 가하여 에틸아세테이트층을 추출한 후 무수 황산마그네슘을 넣고 여과시켜 농축하였다. 농축한 화합물을 실리카 컬럼 크로마토그래피를 사용하여 헥산 : 에틸아세테이트 = 6 : 1 비율의 혼합 용매로 정제하여 50%의 수율로 표제 화합물 1 g을 수득하였다.3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo [b] [1,4] obtained from step 4) above. To 2.96 g (5.12 mmol) of thiazin-8-yl trifluoromethanesulfonate, 60 ml of dimethylformamide, 0.034 g (0.512 mmol) of zinc powder, 0.66 g (5.632 mmol) of zinc cyanide, tris (dibenzylideneacetone) 0.47 g (0.51 mmol) of dipalladium and 0.34 g (0.614 mmol) of 1,1-bis (diphenylphosphino) ferrocene were added thereto and stirred at 80 ° C. for 20 hours. After cooling to room temperature, saturated ammonium chloride solution and ethyl acetate were added to extract the ethyl acetate layer. Anhydrous magnesium sulfate was added thereto, and the filtrate was concentrated. The concentrated compound was purified using silica column chromatography with a mixed solvent of hexane: ethyl acetate = 6: 1 ratio to obtain 1 g of the title compound in a yield of 50%.
1H NMR (400 MHz, CDCl3) δ 8.19 (s, 1H), 7.45 (t, J = 7.6 Hz, 2H), 7.24-7.31 (m, 3H), 6.26 (s, 1H), 4.02 (s, 2H), 3.30 (s, 2H), 2.11 (s, 3H), 1.26-1.58 (m, 4H), 0.83-1.19 (m, 8H), 0.74 (t, J = 6.8 Hz). 1 H NMR (400 MHz, CDCl 3 ) δ 8.19 (s, 1H), 7.45 (t, J = 7.6 Hz, 2H), 7.24-7.31 (m, 3H), 6.26 (s, 1H), 4.02 (s, 2H), 3.30 (s, 2H), 2.11 (s, 3H), 1.26-1.58 (m, 4H), 0.83-1.19 (m, 8H), 0.74 (t, J = 6.8 Hz).
단계 6) 3,3-Step 6) 3,3- 디부틸Dibutyl -7--7- 메틸티오Methylthio -5-페닐-2,3,4,5--5-phenyl-2,3,4,5- 테트라하이드로벤조[b][1,4]티아제핀Tetrahydrobenzo [b] [1,4] thiazepine -8-카브알데하이드 디옥사이드의 제조Preparation of -8-carbaldehyde Dioxide
Figure PCTKR2015009044-appb-I000009
Figure PCTKR2015009044-appb-I000009
상기 단계 5)로부터 수득한 3,3-디부틸-7-메틸티오-5-페닐-2,3,4,5-테트라하이드로벤조[b][1,4]티아제핀-8-카보니트릴 디옥사이드 1 g(2.1 mmol)에 디클로로메탄을 가하고 0℃로 냉각시킨 뒤 디이소부틸알루미늄 하이드라이드(DIBAL-H) 5 ㎖를 천천히 적가하였다. 상온으로 올리고 1시간 동안 교반하였다. 다시 0℃로 냉각시킨 뒤 증류수와 에틸아세테이트, 주석산나트륨칼륨을 넣고 30분 동안 교반하였다. 에틸아세테이트층을 추출한 뒤 무수 황산마그네슘을 넣고 여과하여 농축시켰다. 농축한 화합물을 실리카 컬럼크로마토그래피를 통하여 헥산 : 에틸아세테이트 = 4 : 1 비율의 혼합 용매로 정제시켜 63%의 수율로 표제 화합물 600 ㎎을 수득하였다.3,3-dibutyl-7-methylthio-5-phenyl-2,3,4,5-tetrahydrobenzo [b] [1,4] thiazepine-8-carbonitrile dioxide obtained from step 5) above Dichloromethane was added to 1 g (2.1 mmol), cooled to 0 ° C., and 5 ml of diisobutylaluminum hydride (DIBAL-H) was slowly added dropwise. Raised to room temperature and stirred for 1 hour. After cooling to 0 ° C., distilled water, ethyl acetate, and potassium stannate were added thereto, followed by stirring for 30 minutes. After extracting the ethyl acetate layer, anhydrous magnesium sulfate was added, filtered and concentrated. The concentrated compound was purified by silica column chromatography with a mixed solvent of hexane: ethyl acetate = 4: 1 ratio to obtain 600 mg of the title compound in a yield of 63%.
1H NMR (400 MHz, CDCl3) δ 9.91 (s, 1H), 8.37 (s, 1H), 7.46 (t, J = 7.6 Hz, 2H), 7.26-7.30 (m, 3H), 6.27 (s, 1H), 4.08 (s, 2H), 3.34 (s, 2H), 0.88-1.40 (m, 12H), 0.77 (t, J = 6.8 Hz). 1 H NMR (400 MHz, CDCl 3 ) δ 9.91 (s, 1H), 8.37 (s, 1H), 7.46 (t, J = 7.6 Hz, 2H), 7.26-7.30 (m, 3H), 6.27 (s, 1H), 4.08 (s, 2H), 3.34 (s, 2H), 0.88-1.40 (m, 12H), 0.77 (t, J = 6.8 Hz).
실시예Example 1: 21: 2 -(((3,3--(((3,3- 디부틸Dibutyl -7--7- 메틸티오Methylthio -1,1--1,1- 디옥시도Deoxydo -5-페닐-2,3,4,5--5-phenyl-2,3,4,5- 테트라하이드로벤조[b][1,4]티아제핀Tetrahydrobenzo [b] [1,4] thiazepine -8-일)메틸)아미노)아세트산의 제조Preparation of -8-yl) methyl) amino) acetic acid
Figure PCTKR2015009044-appb-I000010
Figure PCTKR2015009044-appb-I000010
상기 제조예 1로부터 수득한 3,3-디부틸-7-메틸티오-5-페닐-2,3,4,5-테트라하이드로벤조[b][1,4]티아제핀-8-카브알데하이드 디옥사이드 31 ㎎(0.067 mmol)을 디클로로에탄 2 ㎖에 넣고 에틸 글리신 메틸 에스테르 염산염 11 ㎎(0.088 mmol)을 투입한 후, 상온에서 20분 동안 교반하였다. 소듐 트리아세톡시보로하이드라이드 28 ㎎(0.131 mmol)을 투입하고 상온에서 17시간 동안 교반하였다. 반응이 완료되면 디클로로메탄과 증류수를 가하여 추출하고 무수 황산마그네슘으로 건조하고 여과하여 감압농축하였다. 여액을 PTLC(디클로로메탄 : 메탄올 = 50 : 1)로 정제하여 에틸 2-(((3,3-디부틸-7-메틸티오-1,1-디옥시도-5-페닐-2,3,4,5-테트라하이드로벤조[b][1,4]티아제핀-8-일)메틸)아미노)아세테이트 20.5 ㎎(수율 57%)을 수득하였다.3,3-Dibutyl-7-methylthio-5-phenyl-2,3,4,5-tetrahydrobenzo [b] [1,4] thiazepine-8-carbaldehyde dioxide obtained from Preparation Example 1 31 mg (0.067 mmol) was added to 2 ml of dichloroethane, and 11 mg (0.088 mmol) of ethyl glycine methyl ester hydrochloride was added thereto, followed by stirring at room temperature for 20 minutes. 28 mg (0.131 mmol) of sodium triacetoxyborohydride was added thereto, followed by stirring at room temperature for 17 hours. After the reaction was completed, dichloromethane and distilled water were added for extraction, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The filtrate was purified by PTLC (dichloromethane: methanol = 50: 1) to obtain ethyl 2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3, 20.5 mg (yield 57%) of 4,5-tetrahydrobenzo [b] [1,4] thiazepin-8-yl) methyl) amino) acetate were obtained.
상기 수득한 화합물 20.5 ㎎(0.038 mmol)을 테트라하이드로퓨란 : 메탄올 : 증류수 = 1 : 1 : 1 용액 3 ㎖에 넣고 수산화리튬 16 ㎎(0.40 mmol)을 투입한 후, 상온에서 12시간 동안 교반하였다. 반응이 완료되면 에틸아세테이트와 1N 염산을 가하여 추출하고 무수 황산마그네슘으로 건조하고 여과하여 감압농축하였다. 여액을 PTLC(디클로로메탄 : 메탄올 = 20 : 1)로 정제하여 표제 화합물 2-(((3,3-디부틸-7-메틸티오-1,1-디옥시도-5-페닐-2,3,4,5-테트라하이드로벤조[b][1,4]티아제핀-8-일)메틸)아미노)아세트산 10 ㎎(수율 44%)을 수득하였다.20.5 mg (0.038 mmol) of the obtained compound was added to 3 ml of a solution of tetrahydrofuran: methanol: distilled water = 1: 1: 1, and 16 mg (0.40 mmol) of lithium hydroxide was added thereto, followed by stirring at room temperature for 12 hours. After the reaction was completed, ethyl acetate and 1N hydrochloric acid were added for extraction, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The filtrate was purified by PTLC (dichloromethane: methanol = 20: 1) to give the title compound 2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3 10 mg (yield 44%) of 4,5-tetrahydrobenzo [b] [1,4] thiazepin-8-yl) methyl) amino) acetic acid were obtained.
1H NMR (400 MHz, CDCl3) δ 8.22 (s, 1H), 7.34 (t, J = 7.6 Hz, 2H), 7.24 (t, J = 7.6 Hz, 2H), 7.12 (t, J = 7.6 Hz, 1H), 6.47 (s, 1H), 4.46 (s, 2H), 3.73-3.93 (m, 4H), 3.33 (s, 2H), 2.15 (s, 3H), 1.47-1.52 (m, 2H), 1.33-1.39 (m, 2H), 1.08-1.15 (m, 4H), 1.00-1.03 (m, 4H), 0.78 (t, J = 6.8 Hz, 6H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.22 (s, 1H), 7.34 (t, J = 7.6 Hz, 2H), 7.24 (t, J = 7.6 Hz, 2H), 7.12 (t, J = 7.6 Hz , 1H), 6.47 (s, 1H), 4.46 (s, 2H), 3.73-3.93 (m, 4H), 3.33 (s, 2H), 2.15 (s, 3H), 1.47-1.52 (m, 2H), 1.33-1.39 (m, 2H), 1.08-1.15 (m, 4H), 1.00-1.03 (m, 4H), 0.78 (t, J = 6.8 Hz, 6H).
실시예Example 2: 32: 3 -(((3,3--(((3,3- 디부틸Dibutyl -7--7- 메틸티오Methylthio -1,1--1,1- 디옥시도Deoxydo -5-페닐-2,3,4,5--5-phenyl-2,3,4,5- 테트라하이드로벤조[b][1,4]티아제핀Tetrahydrobenzo [b] [1,4] thiazepine -8-일)메틸)아미노)프로판산의 제조Preparation of -8-yl) methyl) amino) propanoic acid
Figure PCTKR2015009044-appb-I000011
Figure PCTKR2015009044-appb-I000011
반응물로서 에틸 글리신 메틸 에스테르 염산염 대신에 에틸 3-아미노프로파노에이트를 사용하는 것을 제외하고는 실시예 1과 유사한 방법으로 상기 표제 화합물을 합성하였다(수율 65%).The title compound was synthesized in a similar manner to Example 1 except for using ethyl 3-aminopropanoate instead of ethyl glycine methyl ester hydrochloride as the reaction (yield 65%).
1H NMR (400 MHz, CDCl3) δ 8.14 (s, 1H), 7.38-7.34 (m, 2H), 7.26-7.22 (m, 2H), 7.17-6.97 (m, 1H), 6.46 (s, 1H), 4.35 (s, 2H), 3.88 (s, 2H), 3.26 (s, 4H), 2.93 (s, 2H), 2.15 (s, 3H), 1.60-1.46 (m, 2H), 1.40-1.29 (m, 2H), 1.14-0.99 (m, 8H), 0.81-0.74 (m, 6H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.14 (s, 1H), 7.38-7.34 (m, 2H), 7.26-7.22 (m, 2H), 7.17-6.97 (m, 1H), 6.46 (s, 1H ), 4.35 (s, 2H), 3.88 (s, 2H), 3.26 (s, 4H), 2.93 (s, 2H), 2.15 (s, 3H), 1.60-1.46 (m, 2H), 1.40-1.29 ( m, 2H), 1.14-0.99 (m, 8H), 0.81-0.74 (m, 6H).
실시예Example 3: 23: 2 -(((3,3--(((3,3- 디부틸Dibutyl -7--7- 메틸티오Methylthio -1,1--1,1- 디옥시도Deoxydo -5-페닐-2,3,4,5--5-phenyl-2,3,4,5- 테트라하이드로벤조[b][1,4]티아제핀Tetrahydrobenzo [b] [1,4] thiazepine -8-일)메틸)아미노)숙신산의 제조Preparation of -8-yl) methyl) amino) succinic acid
Figure PCTKR2015009044-appb-I000012
Figure PCTKR2015009044-appb-I000012
반응물로서 에틸 글리신 메틸 에스테르 염산염 대신에 디에틸 아스팔테이트를 사용하는 것을 제외하고는 실시예 1과 유사한 방법으로 상기 표제 화합물을 합성하였다(수율 52%).The title compound was synthesized in a similar manner to Example 1 except that diethyl asphaltate was used instead of ethyl glycine methyl ester hydrochloride as the reaction (yield 52%).
1H NMR (400 MHz, CDCl3) δ 8.21 (s, 1H), 7.34 (s, 3H), 7.24 (s, 1H), 7.12 (s, 1H), 6.46 (s, 1H), 4.62-4.35 (m, 2H), 4.02-3.88 (m, 2H), 3.50-3.10 (m, 5H), 2.17 (s, 3H), 1.66-1.35 (m, 4H), 1.22-0.89 (m, 8H), 0.75 (s, 6H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.21 (s, 1H), 7.34 (s, 3H), 7.24 (s, 1H), 7.12 (s, 1H), 6.46 (s, 1H), 4.62-4.35 ( m, 2H), 4.02-3.88 (m, 2H), 3.50-3.10 (m, 5H), 2.17 (s, 3H), 1.66-1.35 (m, 4H), 1.22-0.89 (m, 8H), 0.75 ( s, 6H).
실시예Example 4: (S)-2-(((3,3- 4: (S) -2-(((3,3- 디부틸Dibutyl -7--7- 메틸티오Methylthio -1,1--1,1- 디옥시도Deoxydo -5-페닐-2,3,4,5--5-phenyl-2,3,4,5- 테트라하이드로벤조[b][1,4]티아제핀Tetrahydrobenzo [b] [1,4] thiazepine -8-일)메틸)아미노)프로판산의 제조Preparation of -8-yl) methyl) amino) propanoic acid
Figure PCTKR2015009044-appb-I000013
Figure PCTKR2015009044-appb-I000013
반응물로서 에틸 글리신 메틸 에스테르 염산염 대신에 디에틸 알라닌 에스테르를 사용하는 것을 제외하고는 실시예 1과 유사한 방법으로 상기 표제 화합물을 합성하였다(수율 61%).The title compound was synthesized in a similar manner to Example 1 except for using diethyl alanine ester in place of ethyl glycine methyl ester hydrochloride as the reaction (yield 61%).
1H NMR (400 MHz, CDCl3) δ 8.16 (s, 1H), 7.32 (s, 2H), 7.16-7.12 (m, 3H), 6.45 (s, 1H), 4.24-4.19 (m, 2H), 3.81 (s, 2H), 3.52 (s, 1H), 3.27 (s, 2H), 2.09 (s, 3H), 1.52-1.42 (m, 5H), 1.41-1.25 (m, 2H), 1.24-0.92 (m, 8H), 0.88-0.65 (m, 6H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.16 (s, 1H), 7.32 (s, 2H), 7.16-7.12 (m, 3H), 6.45 (s, 1H), 4.24-4.19 (m, 2H), 3.81 (s, 2H), 3.52 (s, 1H), 3.27 (s, 2H), 2.09 (s, 3H), 1.52-1.42 (m, 5H), 1.41-1.25 (m, 2H), 1.24-0.92 ( m, 8H), 0.88-0.65 (m, 6H).
실시예Example 5: 25: 2 -(((3,3--(((3,3- 디부틸Dibutyl -7--7- 메틸티오Methylthio -1,1--1,1- 디옥시도Deoxydo -5-페닐-2,3,4,5--5-phenyl-2,3,4,5- 테트라하이드로벤조[b][1,4]티아제핀Tetrahydrobenzo [b] [1,4] thiazepine -8-일)메틸)아미노)펜탄디오산의 제조Preparation of -8-yl) methyl) amino) pentanedioic acid
Figure PCTKR2015009044-appb-I000014
Figure PCTKR2015009044-appb-I000014
반응물로서 에틸 글리신 메틸 에스테르 염산염 대신에 디에틸 글루타민 에스테르를 사용하는 것을 제외하고는 실시예 1과 유사한 방법으로 상기 표제 화합물을 합성하였다(수율 36%).The title compound was synthesized in a similar manner to Example 1 except for using diethyl glutamine ester in place of ethyl glycine methyl ester hydrochloride as the reaction (yield 36%).
1H NMR (400 MHz, CDCl3) δ 7.74 (s, 1H), 7.35-7.33 (m, 2H), 7.19-7.18 (m, 2H), 7.12-7.09 (m, 1H), 6.43 (s, 1H), 4.97 (d, J = 14 Hz, 1H), 4.17 (d, J = 15.2 Hz, 1H), 3.85 (s, 3H), 3.26 (s, 2H), 1.21-0.96 (m, 8H), 0.82-0.76 (m, 6H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.74 (s, 1H), 7.35-7.33 (m, 2H), 7.19-7.18 (m, 2H), 7.12-7.09 (m, 1H), 6.43 (s, 1H ), 4.97 (d, J = 14 Hz, 1H), 4.17 (d, J = 15.2 Hz, 1H), 3.85 (s, 3H), 3.26 (s, 2H), 1.21-0.96 (m, 8H), 0.82 -0.76 (m, 6 H).
실시예Example 6: 46: 4 -아미노-2-(((3,3--Amino-2-(((3,3- 디부틸Dibutyl -7--7- 메틸티오Methylthio -1,1--1,1- 디옥시도Deoxydo -5-페닐-2,3,4,5-테트라하이드로벤조[b][1,4]티아제핀-8-일)메틸)아미노)-4-옥소부탄산의 제조Preparation of -5-phenyl-2,3,4,5-tetrahydrobenzo [b] [1,4] thiazepin-8-yl) methyl) amino) -4-oxobutanoic acid
Figure PCTKR2015009044-appb-I000015
Figure PCTKR2015009044-appb-I000015
반응물로서 에틸 글리신 메틸 에스테르 염산염 대신에 디에틸 알지닌 에스테르를 사용하는 것을 제외하고는 실시예 1과 유사한 방법으로 상기 표제 화합물을 합성하였다(수율 23%).The title compound was synthesized in a similar manner to Example 1 except for using diethyl alginine ester in place of ethyl glycine methyl ester hydrochloride as the reaction (yield 23%).
MS : 576.25 [M+H]+.MS: 576.25 [M + H] + .
실시예Example 7: (R)-2-(((3,3- 7: (R) -2-(((3,3- 디부틸Dibutyl -7--7- 메틸티오Methylthio -1,1--1,1- 디옥시도Deoxydo -5-페닐-2,3,4,5--5-phenyl-2,3,4,5- 테트라하이드로벤조[b][1,4]티아제핀Tetrahydrobenzo [b] [1,4] thiazepine -8-일)메틸)아미노)프로판산의 제조Preparation of -8-yl) methyl) amino) propanoic acid
Figure PCTKR2015009044-appb-I000016
Figure PCTKR2015009044-appb-I000016
반응물로서 에틸 글리신 메틸 에스테르 염산염 대신에 디에틸 알라닌 에스테르를 사용하는 것을 제외하고는 실시예 1과 유사한 방법으로 상기 표제 화합물을 합성하였다(수율 56%).The title compound was synthesized in a similar manner to Example 1 except for using diethyl alanine ester in place of ethyl glycine methyl ester hydrochloride as the reaction (yield 56%).
1H NMR (400 MHz, CDCl3) δ 8.00 (s, 1H), 7.19-7.26 (m, 2H), 7.08-7.10 (m, 3H), 6.38 (s, 1H), 4.03-7.09 (m, 2H), 3.76 (s, 2H), 3.41 (s, 1H), 3.20 (s, 2H), 2.89-2.99 (m, 1H), 2.02 (s, 3H), 1.43 (s, 3H), 1.29-1.36 (m, 2H), 1.18-1.23 (m, 2H), 0.81-1.08 (m, 8H), 0.69-0.7 (m, 6H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.00 (s, 1H), 7.19-7.26 (m, 2H), 7.08-7.10 (m, 3H), 6.38 (s, 1H), 4.03-7.09 (m, 2H ), 3.76 (s, 2H), 3.41 (s, 1H), 3.20 (s, 2H), 2.89-2.99 (m, 1H), 2.02 (s, 3H), 1.43 (s, 3H), 1.29-1.36 ( m, 2H), 1.18-1.23 (m, 2H), 0.81-1.08 (m, 8H), 0.69-0.7 (m, 6H).
실시예Example 8: 28: 2 -(((3,3--(((3,3- 디부틸Dibutyl -7--7- 메틸티오Methylthio -1,1--1,1- 디옥시도Deoxydo -5-페닐-2,3,4,5--5-phenyl-2,3,4,5- 테트라하이드로벤조[b][1,4]티아제핀Tetrahydrobenzo [b] [1,4] thiazepine -8-일)메틸)아미노)-2-메틸프로판산의 제조Preparation of -8-yl) methyl) amino) -2-methylpropanoic acid
Figure PCTKR2015009044-appb-I000017
Figure PCTKR2015009044-appb-I000017
반응물로서 에틸 글리신 메틸 에스테르 염산염 대신에 에틸 2-아미노-2-메틸프로파노에이트를 사용하는 것을 제외하고는 실시예 1과 유사한 방법으로 상기 표제 화합물을 합성하였다(수율 57%).The title compound was synthesized in a similar manner to Example 1 except for using ethyl 2-amino-2-methylpropanoate instead of ethyl glycine methyl ester hydrochloride as the reaction (yield 57%).
1H NMR (400 MHz, CDCl3) δ 7.99 (s, 1H), 7.33 (t, J = 7.6 Hz, 2H), 7.17-7.18 (m, 2H), 7.11-7.12 (m, 1H), 6.48 (s, 1H), 3.96 (s, 2H), 3.81 (s, 2H), 3.21 (s, 2H), 2.14 (s, 3H), 1.53 (s, 6H), 1.25-1.34 (m, 4H), 0.85-1.14 (m, 8H), 0.76 (t, J = 6.8 Hz, 6H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.99 (s, 1H), 7.33 (t, J = 7.6 Hz, 2H), 7.17-7.18 (m, 2H), 7.11-7.12 (m, 1H), 6.48 ( s, 1H), 3.96 (s, 2H), 3.81 (s, 2H), 3.21 (s, 2H), 2.14 (s, 3H), 1.53 (s, 6H), 1.25-1.34 (m, 4H), 0.85 -1.14 (m, 8H), 0.76 (t, J = 6.8 Hz, 6H).
실시예Example 9: (R)-2-(((3,3-디부틸-7-메틸티오-1,1-디옥시도-5-페닐-2,3,4,5-테트라하이드로벤조[b][1,4]티아제핀-8-일)메틸)아미노)-3-(1H-이미다졸-4-일)프로판산의 제조 9: (R) -2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo [b] [ Preparation of 1,4] thiazepin-8-yl) methyl) amino) -3- (1H-imidazol-4-yl) propanoic acid
Figure PCTKR2015009044-appb-I000018
Figure PCTKR2015009044-appb-I000018
반응물로서 에틸 글리신 메틸 에스테르 염산염 대신에 에틸 히스티딘 에스테르를 사용하는 것을 제외하고는 실시예 1과 유사한 방법으로 상기 표제 화합물을 합성하였다(수율 43%).The title compound was synthesized in a similar manner to Example 1 except for using ethyl histidine ester instead of ethyl glycine methyl ester hydrochloride as the reaction (yield 43%).
1H NMR (400 MHz, CDCl3) δ 7.77 (s, 1H), 7.54 (s, 1H), 7.28-7.30 (m, 2H), 7.04-7.11 (m, 3H), 6.78 (s, 1H), 6.38 (s, 1H), 3.78 (s, 4H), 3.41-4.11 (m, 2H), 3.18 (s, 2H), 2.94-2.98 (m, 1H), 1.86 (s, 3H), 1.27-1.43 (m, 4H), 0.82-1.10 (m, 8H), 0.71 (t, J = 6.8 Hz, 6H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.77 (s, 1H), 7.54 (s, 1H), 7.28-7.30 (m, 2H), 7.04-7.11 (m, 3H), 6.78 (s, 1H), 6.38 (s, 1H), 3.78 (s, 4H), 3.41-4.11 (m, 2H), 3.18 (s, 2H), 2.94-2.98 (m, 1H), 1.86 (s, 3H), 1.27-1.43 ( m, 4H), 0.82-1.10 (m, 8H), 0.71 (t, J = 6.8 Hz, 6H).
실시예Example 10: (R)-2-(((3,3-디부틸-7-메틸티오-1,1-디옥시도-5-페닐-2,3,4,5-테트라하이드로벤조[b][1,4]티아제핀-8-일)메틸)아미노)-3-(1H-인돌-2-일)프로판산의 제조 10: (R) -2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo [b] [ Preparation of 1,4] thiazepin-8-yl) methyl) amino) -3- (1H-indol-2-yl) propanoic acid
Figure PCTKR2015009044-appb-I000019
Figure PCTKR2015009044-appb-I000019
반응물로서 에틸 글리신 메틸 에스테르 염산염 대신에 에틸 트립토판 에스테르를 사용하는 것을 제외하고는 실시예 1과 유사한 방법으로 상기 표제 화합물을 합성하였다(수율 37%).The title compound was synthesized in a similar manner to Example 1 except that ethyl tryptophan ester was used instead of ethyl glycine methyl ester hydrochloride as the reaction (yield 37%).
MS: 648.29 [M+H]+.MS: 648.29 [M + H] + .
실시예Example 11: (S)-2-(((3,3- 11: (S) -2-(((3,3- 디부틸Dibutyl -7--7- 메틸티오Methylthio -1,1--1,1- 디옥시도Deoxydo -5-페닐-2,3,4,5-테트라하이드로벤조[b][1,4]티아제핀-8-일)메틸)아미노)-4-메틸펜탄산의 제조Preparation of 5-5-phenyl-2,3,4,5-tetrahydrobenzo [b] [1,4] thiazepin-8-yl) methyl) amino) -4-methylpentanoic acid
Figure PCTKR2015009044-appb-I000020
Figure PCTKR2015009044-appb-I000020
반응물로서 에틸 글리신 메틸 에스테르 염산염 대신에 에틸 루이신 에스테르를 사용하는 것을 제외하고는 실시예 1과 유사한 방법으로 상기 표제 화합물을 합성하였다(수율 58%).The title compound was synthesized in a similar manner to Example 1 except for using ethyl leucine ester instead of ethyl glycine methyl ester hydrochloride as the reaction (yield 58%).
MS: 575.29 [M+H]+.MS: 575.29 [M + H] + .
실시예Example 12: (S)-2-(((3,3- 12: (S) -2-(((3,3- 디부틸Dibutyl -7--7- 메틸티오Methylthio -1,1--1,1- 디옥시도Deoxydo -5-페닐-2,3,4,5-테트라하이드로벤조[b][1,4]티아제핀-8-일)메틸)아미노)펜탄디오산의 제조Preparation of -5-phenyl-2,3,4,5-tetrahydrobenzo [b] [1,4] thiazepin-8-yl) methyl) amino) pentanedioic acid
Figure PCTKR2015009044-appb-I000021
Figure PCTKR2015009044-appb-I000021
반응물로서 에틸 글리신 메틸 에스테르 염산염 대신에 디에틸 글루타민 에스테르를 사용하는 것을 제외하고는 실시예 1과 유사한 방법으로 상기 표제 화합물을 합성하였다(수율 25%).The title compound was synthesized in a similar manner to Example 1 except that diethyl glutamine ester was used instead of ethyl glycine methyl ester hydrochloride as the reaction (yield 25%).
MS: 591.27 [M+H]+.MS: 591.27 [M + H] + .
실시예Example 13: (S)-2-(((3,3- 13: (S) -2-(((3,3- 디부틸Dibutyl -7--7- 메틸티오Methylthio -1,1--1,1- 디옥시도Deoxydo -5-페닐-2,3,4,5-테트라하이드로벤조[b][1,4]티아제핀-8-일)메틸)아미노)-3-히드록시프로판산의 제조Preparation of -5-phenyl-2,3,4,5-tetrahydrobenzo [b] [1,4] thiazepin-8-yl) methyl) amino) -3-hydroxypropanoic acid
Figure PCTKR2015009044-appb-I000022
Figure PCTKR2015009044-appb-I000022
반응물로서 에틸 글리신 메틸 에스테르 염산염 대신에 디에틸 세린 에스테르를 사용하는 것을 제외하고는 실시예 1과 유사한 방법으로 상기 표제 화합물을 합성하였다(수율 45%).The title compound was synthesized in a similar manner to Example 1 except for using diethyl serine ester instead of ethyl glycine methyl ester hydrochloride as the reaction (yield 45%).
MS: 549.25 [M+H]+.MS: 549.25 [M + H] + .
실시예Example 14: 314: 3 -((-(( 카복시메틸Carboxymethyl )((3,3-) ((3,3- 디부틸Dibutyl -7--7- 메틸티오Methylthio -1,1--1,1- 디옥시도Deoxydo -5-페닐-2,3,4,5-테트라하이드로벤조[b][1,4]티아제핀-8-일)메틸)아미노)프로판산의 제조Preparation of -5-phenyl-2,3,4,5-tetrahydrobenzo [b] [1,4] thiazepin-8-yl) methyl) amino) propanoic acid
Figure PCTKR2015009044-appb-I000023
Figure PCTKR2015009044-appb-I000023
반응물로서 에틸 글리신 메틸 에스테르 염산염 대신에 3-((2-에톡시-2-옥소에틸)아미노)프로파노에이트를 사용하는 것을 제외하고는 실시예 1과 유사한 방법으로 상기 표제 화합물을 합성하였다(수율 49%).The title compound was synthesized in a similar manner to Example 1 except for using 3-((2-ethoxy-2-oxoethyl) amino) propanoate instead of ethyl glycine methyl ester hydrochloride as the reaction (yield) 49%).
1H NMR (400 MHz, CDCl3) δ 8.16 (s, 1H), 7.34-7.43 (m, 2H), 7.27 (s, 2H), 7.12-7.16 (m, 1H), 6.45 (s, 1H), 4.60-4.72 (m, 2H), 4.48-4.59 (m, 2H), 4.00-4.13 (m, 2H), 3.34 (s, 2H), 3.12-3.23 (m, 2H), 2.14 (s, 3H), 1.36-1.60 (m, 4H), 1.24-1.30 (m, 8H), 0.71 (t, J = 6.8 Hz, 6H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.16 (s, 1H), 7.34-7.43 (m, 2H), 7.27 (s, 2H), 7.12-7.16 (m, 1H), 6.45 (s, 1H), 4.60-4.72 (m, 2H), 4.48-4.59 (m, 2H), 4.00-4.13 (m, 2H), 3.34 (s, 2H), 3.12-3.23 (m, 2H), 2.14 (s, 3H), 1.36-1.60 (m, 4H), 1.24-1.30 (m, 8H), 0.71 (t, J = 6.8 Hz, 6H).
실시예Example 15: 315: 3 -(((3,3--(((3,3- 디부틸Dibutyl -7--7- 메틸티오Methylthio -1,1--1,1- 디옥시도Deoxydo -5-페닐-2,3,4,5--5-phenyl-2,3,4,5- 테트라하이드로벤조[b][1,4]티아제핀Tetrahydrobenzo [b] [1,4] thiazepine -8-일)메틸)아미노)펜탄디오산의 제조Preparation of -8-yl) methyl) amino) pentanedioic acid
Figure PCTKR2015009044-appb-I000024
Figure PCTKR2015009044-appb-I000024
반응물로서 에틸 글리신 메틸 에스테르 염산염 대신에 디에틸 2,2'-아잔디일디아세테이트를 사용하는 것을 제외하고는 실시예 1과 유사한 방법으로 상기 표제 화합물을 합성하였다(수율 41%).The title compound was synthesized in a similar manner to Example 1 except for using diethyl 2,2′-azanediyldiacetate instead of ethyl glycine methyl ester hydrochloride as the reaction (yield 41%).
1H NMR (400 MHz, CDCl3) δ 8.02 (s, 1H), 7.32 (t, J = 7.6 Hz, 2H), 7.21 (d, J = 7.2 Hz , 2H), 7.10 (t, J = 6.8 Hz, 1H), 6.48 (s, 1H), 4.47 (s, 2H), 4.03 (s, 1H), 3.85 (m, 2H), 3.29 (s, 2H), 3.06-3.17 (m, 4H), 2.16 (s, 3H), 1.35-1.46 (m, 4H), 1.23-1.32 (m, 8H), 0.71 (t, J = 6.8 Hz, 6H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.02 (s, 1H), 7.32 (t, J = 7.6 Hz, 2H), 7.21 (d, J = 7.2 Hz, 2H), 7.10 (t, J = 6.8 Hz , 1H), 6.48 (s, 1H), 4.47 (s, 2H), 4.03 (s, 1H), 3.85 (m, 2H), 3.29 (s, 2H), 3.06-3.17 (m, 4H), 2.16 ( s, 3H), 1.35-1.46 (m, 4H), 1.23-1.32 (m, 8H), 0.71 (t, J = 6.8 Hz, 6H).
실시예Example 16: 216: 2 -(((3,3--(((3,3- 디부틸Dibutyl -7--7- 메틸티오Methylthio -1,1--1,1- 디옥시도Deoxydo -5-페닐-2,3,4,5--5-phenyl-2,3,4,5- 테트라하이드로벤조[b][1,4]티아제핀Tetrahydrobenzo [b] [1,4] thiazepine -8-일)메틸)아미노)-2-옥소아세트산의 제조Preparation of -8-yl) methyl) amino) -2-oxoacetic acid
Figure PCTKR2015009044-appb-I000025
Figure PCTKR2015009044-appb-I000025
상기 제조예 1의 단계 5)로부터 수득한 3,3-디부틸-7-메틸티오-5-페닐-2,3,4,5-테트라하이드로벤조[b][1,4]티아제핀-8-카보니트릴 디옥사이드 160 ㎎(0.350 mmol)을 디클로로메탄 : 디에틸에테르 = 3 : 2 용액 5 ㎖에 용해시켰다. 0℃로 냉각시킨 후, 리튬 알루미늄 하이드라이드 66 ㎎(1.752 mmol)을 나누어서 투입하고 상온에서 12시간 동안 교반하였다. 반응이 완료되면, 디에틸에테르와 증류수를 가하여 추출하고 무수 황산마그네슘으로 건조하고 여과하여 감압농축하였다. 여액을 PTLC(디클로로메탄 : 메탄올 = 50 : 1)로 정제하여 8-아미노메틸-3,3-디부틸-7-메틸티오-5-페닐-2,3,4,5-테트라하이드로벤조[b][1,4]티아제핀 디옥사이드 40 ㎎(수율 25%)을 수득하였다.3,3-dibutyl-7-methylthio-5-phenyl-2,3,4,5-tetrahydrobenzo [b] [1,4] thiazepine-8 obtained from step 5) of Preparation Example 1 above. 160 mg (0.350 mmol) of carbonitrile dioxide were dissolved in 5 ml of a dichloromethane: diethylether = 3: 2 solution. After cooling to 0 ° C., 66 mg (1.752 mmol) of lithium aluminum hydride was added in portions, followed by stirring at room temperature for 12 hours. After the reaction was completed, diethyl ether and distilled water were added for extraction, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The filtrate was purified by PTLC (dichloromethane: methanol = 50: 1) to give 8-aminomethyl-3,3-dibutyl-7-methylthio-5-phenyl-2,3,4,5-tetrahydrobenzo [b ] 40 mg (25% yield) of [1,4] thiazepine dioxide were obtained.
상기 수득한 화합물 0.023 g(0.05 mmol)을 디클로로메탄 5 ㎖에 넣고 트리에틸아민 0.01 ㎖(0.1 mmol)와 4-디메틸아미노피리딘 0.003 g을 투입하여 상온에서 10분 동안 교반하였다. 반응액을 0℃로 냉각시킨 후 에틸 2-클로로-2-옥소아세테이트를 천천히 투입하고 상온에서 18시간 동안 교반하였다. 염화암모늄 용액과 디클로로메탄을 가하고 디클로로메탄층을 추출한 후 무수 황산마그네슘으로 건조하고 여과하여 농축하였다. 농축한 화합물 0.02 g에 테트라하이드로퓨란 1 ㎖, 메탄올 1 ㎖, 증류수 1 ㎖를 가하고 수산화리튬 0.03 g을 첨가한 뒤 상온에서 12시간 동안 교반하였다. 이후 6N 염산과 디클로로메탄으로 추출한 후 농축하였다. 농축한 화합물을 PTLC(디클로로메탄 : 메탄올 = 13 : 1)로 정제하여 표제 화합물 2-(((3,3-디부틸-7-메틸티오-1,1-디옥시도-5-페닐-2,3,4,5-테트라하이드로벤조[b][1,4]티아제핀-8-일)메틸)아미노)-2-옥소아세트산 0.015 g(수율 78%)을 수득하였다.0.023 g (0.05 mmol) of the obtained compound was added to 5 mL of dichloromethane, and 0.01 mL (0.1 mmol) of triethylamine and 0.003 g of 4-dimethylaminopyridine were added thereto, followed by stirring at room temperature for 10 minutes. After the reaction solution was cooled to 0 ° C., ethyl 2-chloro-2-oxoacetate was slowly added thereto and stirred at room temperature for 18 hours. Ammonium chloride solution and dichloromethane were added, the dichloromethane layer was extracted, dried over anhydrous magnesium sulfate, filtered and concentrated. 1 mL of tetrahydrofuran, 1 mL of methanol, and 1 mL of distilled water were added to 0.02 g of the concentrated compound, and 0.03 g of lithium hydroxide was added thereto, followed by stirring at room temperature for 12 hours. Then extracted with 6N hydrochloric acid and dichloromethane and concentrated. The concentrated compound was purified by PTLC (dichloromethane: methanol = 13: 1) to give the title compound 2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2 0.015 g (yield 78%) of 3,4,5-tetrahydrobenzo [b] [1,4] thiazepin-8-yl) methyl) amino) -2-oxoacetic acid were obtained.
1H NMR (400 MHz, CDCl3) δ 7.76 (s, 1H), 7.25-7.33 (m, 2H), 6.97-7.11 (m, 3H), 6.50 (s, 1H), 3.72-4.40 (m, 2H), 3.19 (s, 2H), 2.50-2.68 (m, 2H), 2.06 (s, 3H), 1.27-1.43 (m, 4H), 0.93-1.20 (m, 8H), 0.71 (t, J = 6.8 Hz, 6H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.76 (s, 1H), 7.25-7.33 (m, 2H), 6.97-7.11 (m, 3H), 6.50 (s, 1H), 3.72-4.40 (m, 2H ), 3.19 (s, 2H), 2.50-2.68 (m, 2H), 2.06 (s, 3H), 1.27-1.43 (m, 4H), 0.93-1.20 (m, 8H), 0.71 (t, J = 6.8 Hz, 6H).
실시예Example 17: 117: 1 -(((3,3--(((3,3- 디부틸Dibutyl -7--7- 메틸티오Methylthio -1,1--1,1- 디옥시도Deoxydo -5-페닐-2,3,4,5--5-phenyl-2,3,4,5- 테트라하이드로벤조[b][1,4]티아제핀Tetrahydrobenzo [b] [1,4] thiazepine -8-일)메틸)아미노)사이클로프로판카복시산의 제조Preparation of -8-yl) methyl) amino) cyclopropanecarboxylic acid
Figure PCTKR2015009044-appb-I000026
Figure PCTKR2015009044-appb-I000026
반응물로서 에틸 글리신 메틸 에스테르 염산염 대신에 에틸 1-아미노시클로프로판카르복실레이트를 사용하는 것을 제외하고는 실시예 1과 유사한 방법으로 상기 표제 화합물을 합성하였다(수율 52%).The title compound was synthesized in a similar manner to Example 1 except for using ethyl 1-aminocyclopropanecarboxylate instead of ethyl glycine methyl ester hydrochloride as the reaction (yield 52%).
1H NMR (400 MHz, CDCl3) δ 8.11 (s, 1H), 7.42-7.35 (m, 2H), 7.21-7.15 (m, 2H), 7.13-7.12 (m, 1H), 6.49 (s, 1H), 4.53 (s, 2H), 3.88 (s, 2H), 3.24 (s, 2H), 2.04 (s, 3H), 1.68-1.61 (m, 2H), 1.55-1.48 (m, 2H), 1.21-0.92 (m, 12H), 0.78-0.71 (m, 6H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.11 (s, 1H), 7.42-7.35 (m, 2H), 7.21-7.15 (m, 2H), 7.13-7.12 (m, 1H), 6.49 (s, 1H ), 4.53 (s, 2H), 3.88 (s, 2H), 3.24 (s, 2H), 2.04 (s, 3H), 1.68-1.61 (m, 2H), 1.55-1.48 (m, 2H), 1.21- 0.92 (m, 12 H), 0.78-0.71 (m, 6 H).
실시예Example 18: 218: 2 -(((3,3--(((3,3- 디부틸Dibutyl -7--7- 메틸티오Methylthio -1,1--1,1- 디옥시도Deoxydo -5-페닐-2,3,4,5--5-phenyl-2,3,4,5- 테트라하이드로벤조[b][1,4]티아제핀Tetrahydrobenzo [b] [1,4] thiazepine -8-일)메틸)아미노)-2-옥소에탄술폰산의 제조Preparation of -8-yl) methyl) amino) -2-oxoethanesulfonic acid
Figure PCTKR2015009044-appb-I000027
Figure PCTKR2015009044-appb-I000027
상기 실시예 16에서와 동일한 방법으로 8-아미노메틸-3,3-디부틸-7-메틸티오-5-페닐-2,3,4,5-테트라하이드로벤조[b][1,4]티아제핀 디옥사이드를 제조하였다. 상기 화합물 40 ㎎(0.087 mmol)을 디클로로메탄 4 ㎖에 용해시켰다. 0℃로 냉각시킨 후, 트리에틸아민 36 ㎕(0.260 mmol)를 적가하고 10분 동안 교반하였다. 브로모아세틸 염화물 15 ㎕(0.174 mmol)를 천천히 적가하고 상온에서 16시간 동안 교반하였다. 반응이 완료되면 디클로로메탄과 염화암모늄 용액을 가하여 추출하고 무수 황산마그네슘으로 건조하고 여과하여 감압농축하였다. 여액을 PTLC(디클로로메탄 : 메탄올 = 30 : 1)로 정제하여 2-브로모-N-((3,3-디부틸-7-메틸티오-1,1-디옥시도-5-페닐-2,3,4,5-테트라하이드로벤조[b][1,4]티아제핀-8-일)메틸)아세트아미드 25 ㎎(수율 50%)을 수득하였다.In the same manner as in Example 16, 8-aminomethyl-3,3-dibutyl-7-methylthio-5-phenyl-2,3,4,5-tetrahydrobenzo [b] [1,4] thia Zepin dioxide was prepared. 40 mg (0.087 mmol) of the compound was dissolved in 4 ml of dichloromethane. After cooling to 0 ° C., 36 μl (0.260 mmol) of triethylamine was added dropwise and stirred for 10 minutes. 15 μl (0.174 mmol) of bromoacetyl chloride was slowly added dropwise and stirred at room temperature for 16 hours. When the reaction was completed, dichloromethane and ammonium chloride solution was added, extracted, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The filtrate was purified by PTLC (dichloromethane: methanol = 30: 1) to give 2-bromo-N-((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2 25 mg (50% yield) of 3,4,5-tetrahydrobenzo [b] [1,4] thiazepin-8-yl) methyl) acetamide were obtained.
상기 수득한 화합물 25 ㎎(0.043 mmol)을 에탄올 : 증류수 = 1 : 1 용액 3 ㎖에 용해시켰다. 소디움 설파이트 271 ㎎(2.149 mmol)을 투입하고 80℃에서 17시간 동안 교반하였다. 반응이 완료되면 상온으로 냉각시켰다. 에틸아세테이트와 증류수를 가하여 추출하고 무수 황산마그네슘으로 건조하고 여과하여 감압농축하였다. 여액을 PTLC(디클로로메탄 : 메탄올 = 10 : 1)로 정제하여 2-(((3,3-디부틸-7-메틸티오-1,1-디옥시도-5-페닐-2,3,4,5-테트라하이드로벤조[b][1,4]티아제핀-8-일)메틸)아미노)-2-옥소에탄술폰산 12.5 ㎎(수율 50%)을 수득하였다.25 mg (0.043 mmol) of the obtained compound was dissolved in 3 ml of an ethanol: distilled water = 1: 1 solution. 271 mg (2.149 mmol) of sodium sulfite were added and stirred at 80 ° C. for 17 hours. When the reaction was completed it was cooled to room temperature. Ethyl acetate and distilled water were added, extracted, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The filtrate was purified by PTLC (dichloromethane: methanol = 10: 1) to give 2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4 12.5 mg (50% yield) of 5-, tetrahydrobenzo [b] [1,4] thiazepin-8-yl) methyl) amino) -2-oxoethanesulfonic acid were obtained.
MS: 583.20 [M+H]+.MS: 583.20 [M + H] + .
실시예Example 19: 219: 2 -(((3,3--(((3,3- 디부틸Dibutyl -5-(4--5- (4- 메톡시페닐Methoxyphenyl )-7-) -7- 메틸티오Methylthio -1,1--1,1- 디옥시도Deoxydo -2,3,4,5-테트라하이드로벤조[b][1,4]티아제핀-8-일)메틸)아미노)아세트산의 제조Preparation of -2,3,4,5-tetrahydrobenzo [b] [1,4] thiazepin-8-yl) methyl) amino) acetic acid
Figure PCTKR2015009044-appb-I000028
Figure PCTKR2015009044-appb-I000028
상기 제조예 1의 단계 3에서 요오도화 벤젠 대신에 1-아이오도-4-메톡시벤젠을 사용하는 것을 제외하고는 실시예 1의 화합물을 제조하는 것과 유사한 방법으로 표제 화합물을 합성하였다(수율 64%).The title compound was synthesized in a similar manner to the preparation of the compound of Example 1, except that 1-iodo-4-methoxybenzene was used instead of iodoated benzene in Step 3 of Preparation Example 1 (yield 64 %).
1H NMR (400 MHz, CDCl3) δ 8.01 (s, 1H), 7.13-7.15 (m, 2H), 6.80-6.89 (m, 2H), 6.31 (s, 1H), 4.22 (s, 2H), 3.70-3.81 (m, 5H), 3.42 (s, 2H), 3.21 (s, 2H), 2.08 (s, 3H), 1.30-1.55 (m, 4H), 0.86-1.06 (m, 8H), 0.71-0.76 (m, 6H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.01 (s, 1H), 7.13-7.15 (m, 2H), 6.80-6.89 (m, 2H), 6.31 (s, 1H), 4.22 (s, 2H), 3.70-3.81 (m, 5H), 3.42 (s, 2H), 3.21 (s, 2H), 2.08 (s, 3H), 1.30-1.55 (m, 4H), 0.86-1.06 (m, 8H), 0.71- 0.76 (m, 6 H).
실시예Example 20: 220: 2 -(((3,3--(((3,3- 디부틸Dibutyl -5-(4--5- (4- 히드록시페닐Hydroxyphenyl )-7-) -7- 메틸티오Methylthio -1,1--1,1- 디옥시도Deoxydo -2,3,4,5-테트라하이드로벤조[b][1,4]티아제핀-8-일)메틸)아미노)아세트산의 제조Preparation of -2,3,4,5-tetrahydrobenzo [b] [1,4] thiazepin-8-yl) methyl) amino) acetic acid
Figure PCTKR2015009044-appb-I000029
Figure PCTKR2015009044-appb-I000029
상기 제조예 1의 단계 3에서 요오도화 벤젠 대신에 4-아이오도페놀을 사용하는 것을 제외하고는 실시예 1의 화합물을 제조하는 것과 유사한 방법으로 표제 화합물을 합성하였다(수율 37%).The title compound was synthesized in a similar manner to the preparation of the compound of Example 1, except that 4-iodophenol was used instead of iodoated benzene in step 3 of Preparation Example 1 (yield 37%).
1H NMR (400 MHz, CDCl3) δ 7.94 (s, 1H), 7.20 (d, J = 8.8 Hz, 2H), 6.89 (d, J = 8 Hz, 2H), 6.43 (s, 1H), 4.30 (s, 2H), 3.89-3.93 (m, 4H), 3.30-3.36 (m, 2H), 2.21 (s, 3H), 1.40-1.61 (m, 4H), 1.20-1.29 (m, 8H), 0.81 (t, J = 6.8 Hz , 6H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.94 (s, 1H), 7.20 (d, J = 8.8 Hz, 2H), 6.89 (d, J = 8 Hz, 2H), 6.43 (s, 1H), 4.30 (s, 2H), 3.89-3.93 (m, 4H), 3.30-3.36 (m, 2H), 2.21 (s, 3H), 1.40-1.61 (m, 4H), 1.20-1.29 (m, 8H), 0.81 (t, J = 6.8 Hz, 6H).
실시예Example 21: 221: 2 -(((3,3--(((3,3- 디부틸Dibutyl -5-(3--5- (3- 메톡시페닐Methoxyphenyl )-7-) -7- 메틸티오Methylthio -1,1--1,1- 디옥시도Deoxydo -2,3,4,5-테트라하이드로벤조[b][1,4]티아제핀-8-일)메틸)아미노)아세트산의 제조Preparation of -2,3,4,5-tetrahydrobenzo [b] [1,4] thiazepin-8-yl) methyl) amino) acetic acid
Figure PCTKR2015009044-appb-I000030
Figure PCTKR2015009044-appb-I000030
상기 제조예 1의 단계 3에서 요오도화 벤젠 대신에 1-아이오도-3-메톡시벤젠을 사용하는 것을 제외하고는 실시예 1의 화합물을 제조하는 것과 유사한 방법으로 표제 화합물을 합성하였다(수율 47%).The title compound was synthesized in a similar manner to the preparation of the compound of Example 1, except that 1-iodo-3-methoxybenzene was used instead of iodoated benzene in Step 3 of Preparation Example 1 (yield 47 %).
1H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 7.27-7.23 (m, 1H), 6.78-6.67 (m, 2H), 6.66-6.57 (m, 1H), 6.54 (s, 1H), 4.20 (s, 2H), 3.82 (s, 2H), 3.79 (s, 3H), 3.42 (s, 2H), 3.29 (s, 2H), 1.53-1.47 (m, 2H), 1.43-1.32 (m, 2H), 1.24-1.04 (m, 8H), 0.88-0.78 (m, 6H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.05 (s, 1H), 7.27-7.23 (m, 1H), 6.78-6.67 (m, 2H), 6.66-6.57 (m, 1H), 6.54 (s, 1H ), 4.20 (s, 2H), 3.82 (s, 2H), 3.79 (s, 3H), 3.42 (s, 2H), 3.29 (s, 2H), 1.53-1.47 (m, 2H), 1.43-1.32 ( m, 2H), 1.24-1.04 (m, 8H), 0.88-0.78 (m, 6H).
실시예Example 22: 222: 2 -(((3,3--(((3,3- 디부틸Dibutyl -5-(4--5- (4- 플루오로페닐Fluorophenyl )-7-) -7- 메틸티오Methylthio -1,1--1,1- 디옥시도Deoxydo -2,3,4,5-테트라하이드로벤조[b][1,4]티아제핀-8-일)메틸)아미노)아세트산의 제조Preparation of -2,3,4,5-tetrahydrobenzo [b] [1,4] thiazepin-8-yl) methyl) amino) acetic acid
Figure PCTKR2015009044-appb-I000031
Figure PCTKR2015009044-appb-I000031
상기 제조예 1의 단계 3에서 요오도화 벤젠 대신에 1-플루오로-4-아이오도벤젠을 사용하는 것을 제외하고는 실시예 1의 화합물을 제조하는 것과 유사한 방법으로 표제 화합물을 합성하였다.The title compound was synthesized in a similar manner to the preparation of the compound of Example 1, except that 1-fluoro-4-iodobenzene was used instead of iodoated benzene in step 3 of Preparation Example 1.
1H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H), 7.17-7.20 (m, 2H), 7.03 (t, J = 8.4 Hz, 2H), 6.40 (s, 1H), 4.16 (s, 2H), 3.70 (s, 2H), 3.33 (s, 2H), 3.21 (s, 2H), 2.08 (s, 3H), 1.37-1.46 (m, 4H), 0.82-1.06 (m, 8H), 0.77 (t, J = 6.8 Hz, 6H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.12 (s, 1H), 7.17-7.20 (m, 2H), 7.03 (t, J = 8.4 Hz, 2H), 6.40 (s, 1H), 4.16 (s, 2H), 3.70 (s, 2H), 3.33 (s, 2H), 3.21 (s, 2H), 2.08 (s, 3H), 1.37-1.46 (m, 4H), 0.82-1.06 (m, 8H), 0.77 (t, J = 6.8 Hz, 6H).
실시예Example 23: 223: 2 -(((3,3--(((3,3- 디부틸Dibutyl -5-(3--5- (3- 플루오로페닐Fluorophenyl )-7-) -7- 메틸티오Methylthio -1,1--1,1- 디옥시도Deoxydo -2,3,4,5-테트라하이드로벤조[b][1,4]티아제핀-8-일)메틸)아미노)아세트산의 제조Preparation of -2,3,4,5-tetrahydrobenzo [b] [1,4] thiazepin-8-yl) methyl) amino) acetic acid
Figure PCTKR2015009044-appb-I000032
Figure PCTKR2015009044-appb-I000032
상기 제조예 1의 단계 3에서 요오도화 벤젠 대신에 1-플루오로-3-아이오도벤젠을 사용하는 것을 제외하고는 실시예 1의 화합물을 제조하는 것과 유사한 방법으로 표제 화합물을 합성하였다.The title compound was synthesized in a similar manner to the preparation of the compound of Example 1, except that 1-fluoro-3-iodobenzene was used instead of iodoated benzene in Step 3 of Preparation Example 1.
1H NMR (400 MHz, CDCl3) δ 8.15 (s, 1H), 7.23-7.13 (m, 1H), 6.89-6.83 (m, 2H), 6.75-6.71 (m, 1H), 6.65 (s, 1H), 4.27 (s, 2H), 3.73 (s, 2H), 3.52 (s, 2H), 3.26 (s, 2H), 2.20 (s, 3H), 1.57-1.46 (m, 2H), 1.43-1.33 (m, 2H), 1.26-1.07 (m, 8H), 0.86-0.78 (m, 6H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.15 (s, 1H), 7.23-7.13 (m, 1H), 6.89-6.83 (m, 2H), 6.75-6.71 (m, 1H), 6.65 (s, 1H ), 4.27 (s, 2H), 3.73 (s, 2H), 3.52 (s, 2H), 3.26 (s, 2H), 2.20 (s, 3H), 1.57-1.46 (m, 2H), 1.43-1.33 ( m, 2H), 1.26-1.07 (m, 8H), 0.86-0.78 (m, 6H).
실시예Example 24: 2-(((3,3-디부틸-5-(3-플루오로-4-메톡시페닐)-7-메틸티오-1,1-디옥시도-2,3,4,5-테트라하이드로벤조[b][1,4]티아제핀-8-일)메틸)아미노)아세트산의 제조 24: 2-(((3,3-dibutyl-5- (3-fluoro-4-methoxyphenyl) -7-methylthio-1,1-dioxido-2,3,4,5- Preparation of tetrahydrobenzo [b] [1,4] thiazepin-8-yl) methyl) amino) acetic acid
Figure PCTKR2015009044-appb-I000033
Figure PCTKR2015009044-appb-I000033
상기 제조예 1의 단계 3에서 요오도화 벤젠 대신에 2-플루오로-4-아이오도-1-메톡시벤젠을 사용하는 것을 제외하고는 실시예 1의 화합물을 제조하는 것과 유사한 방법으로 표제 화합물을 합성하였다.The title compound was prepared in a similar manner to the preparation of the compound of Example 1, except that 2-fluoro-4-iodo-1-methoxybenzene was used instead of iodoated benzene in step 3 of Preparation Example 1. Synthesized.
1H NMR (400 MHz, CDCl3) δ 8.10 (brs, 1H), 6.70-6.90 (brs, 3H), 6.30-6.50 (brs, 1H), 3.90-4.20 (brs, 2H), 3.30-3.89 (brs, 3H), 3.55-3.29 (brs, 2H), 3.45-2.95 (m, 4H), 1.98-2.22 (brs, 3H), 1.23-1.49 (m, 4H), 0.73-1.24 (8H), 0.73 (brs, 6H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.10 (brs, 1H), 6.70-6.90 (brs, 3H), 6.30-6.50 (brs, 1H), 3.90-4.20 (brs, 2H), 3.30-3.89 (brs , 3H), 3.55-3.29 (brs, 2H), 3.45-2.95 (m, 4H), 1.98-2.22 (brs, 3H), 1.23-1.49 (m, 4H), 0.73-1.24 (8H), 0.73 (brs , 6H).
실시예Example 25: 2-(((3,3-디부틸-5-(4-메톡시페닐)-7-메틸티오-1,1-디옥시도-2,3,4,5-테트라하이드로벤조[b][1,4]티아제핀-8-일)메틸)아미노)-2-옥소에탄술폰산의 제조 25: 2-(((3,3-dibutyl-5- (4-methoxyphenyl) -7-methylthio-1,1-dioxido-2,3,4,5-tetrahydrobenzo [b ] [1,4] thiazepin-8-yl) methyl) amino) -2-oxoethanesulfonic acid
Figure PCTKR2015009044-appb-I000034
Figure PCTKR2015009044-appb-I000034
상기 제조예 1의 단계 3에서 요오도화 벤젠 대신에 1-아이오도-4-메톡시벤젠을 사용하는 것을 제외하고는 실시예 18의 화합물을 제조하는 것과 유사한 방법으로 표제 화합물을 합성하였다.The title compound was synthesized in a similar manner to the preparation of the compound of Example 18, except that 1-iodo-4-methoxybenzene was used instead of iodoated benzene in step 3 of Preparation Example 1.
1H NMR (400 MHz, CDCl3) δ 7.70 (s, 1H), 7.09-6.94 (m, 2H), 6.82-6.64 (m, 2H), 6.27 (s, 1H), 3.80-3.63 (m, 7H), 3.12 (s, 2H), 2.43 (s, 2H), 1.97 (s, 3H), 1.52-1.27 (m, 4H), 1.07-0.88 (m, 8H), 0.82-0.78 (m, 6H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.70 (s, 1H), 7.09-6.94 (m, 2H), 6.82-6.64 (m, 2H), 6.27 (s, 1H), 3.80-3.63 (m, 7H ), 3.12 (s, 2H), 2.43 (s, 2H), 1.97 (s, 3H), 1.52-1.27 (m, 4H), 1.07-0.88 (m, 8H), 0.82-0.78 (m, 6H).
실시예Example 26: 1-(((3,3-디부틸-5-(3-플루오로-4-메톡시페닐)-7-메틸티오-1,1-디옥시도-2,3,4,5-테트라하이드로벤조[b][1,4]티아제핀-8-일)메틸)아미노)사이클로프로판카복시산의 제조 26: 1-(((3,3-dibutyl-5- (3-fluoro-4-methoxyphenyl) -7-methylthio-1,1-dioxido-2,3,4,5- Preparation of tetrahydrobenzo [b] [1,4] thiazepin-8-yl) methyl) amino) cyclopropanecarboxylic acid
Figure PCTKR2015009044-appb-I000035
Figure PCTKR2015009044-appb-I000035
상기 제조예 1의 단계 3에서 요오도화 벤젠 대신에 2-플루오로-4-아이오도-1-메톡시벤젠을 사용하는 것을 제외하고는 실시예 17의 화합물을 제조하는 것과 유사한 방법으로 표제 화합물을 합성하였다.The title compound was prepared in a similar manner to the preparation of the compound of Example 17, except that 2-fluoro-4-iodo-1-methoxybenzene was used instead of iodoated benzene in step 3 of Preparation Example 1. Synthesized.
1H NMR (400 MHz, CDCl3) δ 7.89 (s, 1H), 6.98-6.82 (m, 3H), 6.48 (s, 1H), 3.97 (s, 2H), 3.88 (s, 3H), 3.70 (s, 2H), 3.19 (s, 2H), 2.17 (s, 3H), 1.51-1.32 (m, 4H), 1.20-0.94 (m, 8H), 0.81-0.78 (m, 6H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.89 (s, 1H), 6.98-6.82 (m, 3H), 6.48 (s, 1H), 3.97 (s, 2H), 3.88 (s, 3H), 3.70 ( s, 2H), 3.19 (s, 2H), 2.17 (s, 3H), 1.51-1.32 (m, 4H), 1.20-0.94 (m, 8H), 0.81-0.78 (m, 6H).
실시예Example 27: 227: 2 -(((3,3--(((3,3- 디부틸Dibutyl -5-(4--5- (4- 플루오로페닐Fluorophenyl )-7-) -7- 메틸티오Methylthio -1,1--1,1- 디옥시도Deoxydo -2,3,4,5-테트라하이드로벤조[b][1,4]티아제핀-8-일)메틸)아미노)-2-옥소아세트산의 제조Preparation of -2,3,4,5-tetrahydrobenzo [b] [1,4] thiazepin-8-yl) methyl) amino) -2-oxoacetic acid
Figure PCTKR2015009044-appb-I000036
Figure PCTKR2015009044-appb-I000036
상기 제조예 1의 단계 3에서 요오도화 벤젠 대신에 1-플루오로-4-아이오도벤젠을 사용하는 것을 제외하고는 실시예 16의 화합물을 제조하는 것과 유사한 방법으로 표제 화합물을 합성하였다.The title compound was synthesized in a similar manner to the preparation of the compound of Example 16, except that 1-fluoro-4-iodobenzene was used instead of iodoated benzene in step 3 of Preparation Example 1.
1H NMR (400 MHz, CDCl3) δ 7.72 (s, 1H), 7.10 (brs, 2H), 6.95 (brs, 2H), 6.42 (s, 1H), 4.22-4.36 (m, 2H), 3.66-3.97 (m, 2H), 3.19-3.47 (m, 2H), 2.07 (s, 3H), 1.30-1.33 (m, 4H), 0.88-1.12 (m, 8H), 0.75-0.83 (m, 3H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.72 (s, 1H), 7.10 (brs, 2H), 6.95 (brs, 2H), 6.42 (s, 1H), 4.22-4.36 (m, 2H), 3.66- 3.97 (m, 2H), 3.19-3.47 (m, 2H), 2.07 (s, 3H), 1.30-1.33 (m, 4H), 0.88-1.12 (m, 8H), 0.75-0.83 (m, 3H).
실시예Example 28: (S)-2-(((3,3- 28: (S) -2-(((3,3- 디부틸Dibutyl -5-(4--5- (4- 플루오로페닐Fluorophenyl )-7-) -7- 메틸티오Methylthio -1,1--1,1- 디옥시도Deoxydo -2,3,4,5-테트라하이드로벤조[b][1,4]티아제핀-8-일)메틸)아미노)프로판산의 제조Preparation of -2,3,4,5-tetrahydrobenzo [b] [1,4] thiazepin-8-yl) methyl) amino) propanoic acid
Figure PCTKR2015009044-appb-I000037
Figure PCTKR2015009044-appb-I000037
상기 제조예 1의 단계 3에서 요오도화 벤젠 대신에 1-플루오로-4-아이오도벤젠을 사용하는 것을 제외하고는 실시예 4의 화합물을 제조하는 것과 유사한 방법으로 표제 화합물을 합성하였다.The title compound was synthesized in a similar manner to the preparation of the compound of Example 4, except that 1-fluoro-4-iodobenzene was used instead of iodoated benzene in step 3 of Preparation Example 1.
1H NMR (400 MHz, CDCl3) δ 7.72 (s, 1H), 7.10 (brs, 2H), 6.95 (brs, 2H), 6.42 (s, 1H), 4.22-4.36 (m, 2H), 3.66-3.97 (m, 2H), 3.19-3.47 (m, 2H), 2.07 (s, 3H), 1.30-1.33 (m, 4H), 0.88-1.12 (m, 8H), 0.75-0.83 (m, 3H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.72 (s, 1H), 7.10 (brs, 2H), 6.95 (brs, 2H), 6.42 (s, 1H), 4.22-4.36 (m, 2H), 3.66- 3.97 (m, 2H), 3.19-3.47 (m, 2H), 2.07 (s, 3H), 1.30-1.33 (m, 4H), 0.88-1.12 (m, 8H), 0.75-0.83 (m, 3H).
실시예Example 29: (S)-2-(((3,3-디부틸-5-(4-플루오로페닐)-7-메틸티오-1,1-디옥시도-2,3,4,5-테트라하이드로벤조[b][1,4]티아제핀-8-일)메틸)아미노)-3-히드록시프로판산의 제조 29: (S) -2-(((3,3-dibutyl-5- (4-fluorophenyl) -7-methylthio-1,1-dioxido-2,3,4,5-tetra Preparation of Hydrobenzo [b] [1,4] thiazepin-8-yl) methyl) amino) -3-hydroxypropanoic acid
Figure PCTKR2015009044-appb-I000038
Figure PCTKR2015009044-appb-I000038
상기 제조예 1의 단계 3에서 요오도화 벤젠 대신에 1-플루오로-4-아이오도벤젠을 사용하는 것을 제외하고는 실시예 13의 화합물을 제조하는 것과 유사한 방법으로 표제 화합물을 합성하였다.The title compound was synthesized in a similar manner to the preparation of the compound of Example 13, except that 1-fluoro-4-iodobenzene was used instead of iodoated benzene in Step 3 of Preparation Example 1.
1H NMR (400 MHz, CDCl3) δ 8.15 (s, 1H), 7.17 (brs, 2H), 6.95 (brs, 2H), 6.51 (s, 1H), 4.36 (brs, 2H), 3.95 (brs, 2H), 6.63 (brs, 2H), 3.46 (s, 1H), 3.26 (brs, 2H), 2.01 (s, 3H), 1.25-1.43 (m, 4H), 0.70-0.87 (m, 8H), 0.59-0.67 (m, 3H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.15 (s, 1H), 7.17 (brs, 2H), 6.95 (brs, 2H), 6.51 (s, 1H), 4.36 (brs, 2H), 3.95 (brs, 2H), 6.63 (brs, 2H), 3.46 (s, 1H), 3.26 (brs, 2H), 2.01 (s, 3H), 1.25-1.43 (m, 4H), 0.70-0.87 (m, 8H), 0.59 -0.67 (m, 3 H).
실시예Example 30: 1-(((3,3-디부틸-5-(4-플루오로페닐)-7-메틸티오-1,1-디옥시도-2,3,4,5-테트라하이드로벤조[b][1,4]티아제핀-8-일)메틸)아미노)사이클로프로판카복시산의 제조 30: 1-(((3,3-dibutyl-5- (4-fluorophenyl) -7-methylthio-1,1-dioxido-2,3,4,5-tetrahydrobenzo [b ] [1,4] thiazepin-8-yl) methyl) amino) cyclopropanecarboxylic acid
Figure PCTKR2015009044-appb-I000039
Figure PCTKR2015009044-appb-I000039
상기 제조예 1의 단계 3에서 요오도화 벤젠 대신에 1-플루오로-4-아이오도벤젠을 사용하는 것을 제외하고는 실시예 17의 화합물을 제조하는 것과 유사한 방법으로 표제 화합물을 합성하였다.The title compound was synthesized in a similar manner to the preparation of the compound of Example 17, except that 1-fluoro-4-iodobenzene was used instead of iodoated benzene in step 3 of Preparation Example 1.
1H NMR (400 MHz, CDCl3) δ 7.92 (s, 1H), 7.17-7.14 (m, 2H), 7.09-7.02 (m, 2H), 6.42 (s, 1H), 4.11 (s, 2H), 3.77 (s, 2H), 3.22 (s, 2H), 2.15 (s, 3H), 1.68-1.46 (m, 4H), 1.40-1.30 (m, 4H), 1.21-0.92 (m, 8H), 0.88-0.76 (m, 6H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.92 (s, 1H), 7.17-7.14 (m, 2H), 7.09-7.02 (m, 2H), 6.42 (s, 1H), 4.11 (s, 2H), 3.77 (s, 2H), 3.22 (s, 2H), 2.15 (s, 3H), 1.68-1.46 (m, 4H), 1.40-1.30 (m, 4H), 1.21-0.92 (m, 8H), 0.88- 0.76 (m, 6 H).
실험예Experimental Example 1: 변 배출 시간 및 효율 평가 1: Assessing fecal discharge time and efficiency
8주령 SD 랫트를 구입하여 24℃, 12시간 조명 사육환경에서 7일 동안 순화시켰다. 시험 전날 16시간 동안 절식시키고, 시험 당일 비히클(0.5% 메틸셀룰로오스) 및 0.2 mg/ml 농도로 제조한 시험물질을 각각 5 mg/kg 용량으로 경구 투여하였다. 30분 뒤 바륨을 포함하는 식이 3 g을 경구 투여한 랫트를 대사 케이지에 넣어 10시간 동안 바륨이 장을 통과하여 변으로 배출되는 시간을 각 개체별로 확인하여 기록하였다. 또한, 10시간 내 바륨 변을 배출한 개체의 비율을 개산하여 표 1에 함께 나타내었다.8-week-old SD rats were purchased and allowed to acclimate for 7 days at 24 ° C. in a 12 hour illuminated breeding environment. Fasting was performed for 16 hours the day before the test, and the test substance prepared at vehicle (0.5% methylcellulose) and 0.2 mg / ml concentration was administered orally at a dose of 5 mg / kg each on the test day. After 30 minutes, rats orally administered 3 g of a barium-containing diet were placed in a metabolic cage and recorded for 10 hours for each barium to be discharged into the stool through the intestine. In addition, the ratio of the individuals who discharged the barium stools in 10 hours is shown in Table 1 together.
실시예Example 변 배출 시간 (min) @ 용량 (mg/kg)Stool discharge time (min) @ volume (mg / kg) 10시간 내 변 배출 개체 비율 (%)Percent discharged individuals within 10 hours (%)
매개체Media DD CC
1One C @ 0.1B @ 1A @ 5C @ 0.1B @ 1A @ 5 B @ 0.1A @ 1A @ 5B @ 0.1 A @ 1 A @ 5
1818 B @ 1B @ 1 B @ 1B @ 1
1919 C @ 1B @ 5C @ 1B @ 5 A @ 1A @ 5A @ 1A @ 5
2020 C @ 0.1B @ 1A @ 5C @ 0.1B @ 1A @ 5 A @ 0.1A @ 1A @ 5A @ 0.1 A @ 1 A @ 5
2222 B @ 0.1B @ 1A @ 5B @ 0.1B @ 1A @ 5 A @ 0.1A @ 1A @ 5A @ 0.1 A @ 1 A @ 5
2424 C @ 1A @ 5C @ 1A @ 5 A @ 1A @ 5A @ 1A @ 5
* 변 배출 시간* Stool discharge time
A: 301~400 min, B: 401~500 min, C: 501~590 min, D: 591~600 minA: 301 to 400 min, B: 401 to 500 min, C: 501 to 590 min, D: 591 to 600 min
* 10시간 내 변 배출 개체 비율(%)* Percentage of fecal discharge in 10 hours
A: 76~100%, B: 50~75%, C: ＜50%A: 76-100%, B: 50-75%, C: <50%
변 배출 시간의 단축 및 10시간 내 변 배출 개체율의 증가는 변비 증상의 해소와 밀접한 관계가 있다. 상기 표 1에 나타난 바와 같이, 본 발명에 따른 화합물들을 투여한 실험군 랫트들은 장 기능을 조절하여 변비를 예방하는 것으로 알려진 메틸셀룰로오스 비히클을 투여한 대조군 랫트에 비해 감소된 시간에 변을 배출하였을 뿐만 아니라 10시간 내에 변을 배출한 개체의 비율도 현저히 더 높았다. 또한, 투여 용량을 1/5 내지 1/50 수준까지 낮추어도 비히클과 동등 이상의 효과를 나타냄을 확인하였다. 이는 본 발명의 화합물들이 변비를 효과적으로 예방 또는 치료할 수 있음을 나타내는 것이다.Shortening of stool discharge time and increasing fecal discharge rate within 10 hours are closely related to the elimination of constipation symptoms. As shown in Table 1, the experimental rats administered the compounds according to the present invention not only discharged feces at a reduced time compared to the control rats administered the methylcellulose vehicle known to control bowel function to prevent constipation. The proportion of individuals who excreted feces within 10 hours was also significantly higher. In addition, it was confirmed that even lowering the dose to 1/5 to 1/50 level shows an effect equal to or higher than the vehicle. This indicates that the compounds of the present invention can effectively prevent or treat constipation.

Claims (11)

  1. 하기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염:A compound represented by formula (1) or a pharmaceutically acceptable salt thereof:
    [화학식 1][Formula 1]
    Figure PCTKR2015009044-appb-I000040
    Figure PCTKR2015009044-appb-I000040
    상기 식에서,Where
    R1은 히드록시, 카복시 또는 히드록시설포닐(C1-4 알킬)이고;R 1 is hydroxy, carboxy or hydroxysulfonyl (C 1-4 alkyl);
    R2 및 R3은 각각 독립적으로 수소, C1-4 알킬, 히드록시(C1-4 알킬), 카바모일(C1-4 알킬), 카복시, 카복시(C1-4 알킬), (C5-10 헤테로아릴)(C1-4 알킬) 또는 (C5-10 아릴)(C1-4 알킬)이거나, R2 및 R3이 함께 C3-7 사이클로알킬을 형성하고;R 2 and R 3 are each independently hydrogen, C 1-4 alkyl, hydroxy (C 1-4 alkyl), carbamoyl (C 1-4 alkyl), carboxy, carboxy (C 1-4 alkyl), (C 5-10 heteroaryl) (C 1-4 alkyl) or (C 5-10 aryl) (C 1-4 alkyl) or R 2 and R 3 together form C 3-7 cycloalkyl;
    R4는 수소 또는 카복시(C1-4 알킬)이고;R 4 is hydrogen or carboxy (C 1-4 alkyl);
    R5는 수소, 할로겐, (C1-4 알킬)티오, (C1-4 알킬)아미노 또는 디(C1-4 알킬)아미노이고;R 5 is hydrogen, halogen, (C 1-4 alkyl) thio, (C 1-4 alkyl) amino or di (C 1-4 alkyl) amino;
    R6 및 R7은 각각 독립적으로 C1-6 알킬이고;R 6 and R 7 are each independently C 1-6 alkyl;
    R8 및 R9는 각각 독립적으로 수소, 히드록시, C1-4 알콕시, C1-4 알킬, 할로겐, 니트로, 시아노, 아미노, (C1-4 알킬)아미노, 디(C1-4 알킬)아미노, 아세트아미도, 포르밀, C1-4 알카노일, 카복시, 카바모일, (C1-4 알킬)카바모일, 디(C1-4 알킬)카바모일, 카바모일옥시, (C1-4 알킬)카바모일옥시, 디(C1-4 알킬)카바모일옥시, (C1-4 알킬)설포닐옥시, 설파모일옥시, (C1-4 알킬)설파모일옥시 또는 디(C1-4 알킬)설파모일옥시이고;R 8 and R 9 are each independently hydrogen, hydroxy, C 1-4 alkoxy, C 1-4 alkyl, halogen, nitro, cyano, amino, (C 1-4 alkyl) amino, di (C 1-4 Alkyl) amino, acetamido, formyl, C 1-4 alkanoyl, carboxy, carbamoyl, (C 1-4 alkyl) carbamoyl, di (C 1-4 alkyl) carbamoyl, carbamoyloxy, (C 1-4 alkyl) carbamoyloxy, di (C 1-4 alkyl) carbamoyloxy, (C 1-4 alkyl) sulfonyloxy, sulfamoyloxy, (C 1-4 alkyl) sulfamoyloxy or di (C 1-4 alkyl) sulfamoyloxy;
    Q는 C5-10 아릴 또는 C5-10 헤테로아릴이고;Q is C 5-10 aryl or C 5-10 heteroaryl;
    n은 0 내지 3의 정수이다.n is an integer of 0-3.
  2. 제1항에 있어서,The method of claim 1,
    R1은 히드록시, 카복시 또는 히드록시설포닐(C1-4 알킬)이고;R 1 is hydroxy, carboxy or hydroxysulfonyl (C 1-4 alkyl);
    R2 및 R3은 각각 독립적으로 수소, C1-4 알킬, 히드록시(C1-4 알킬), 카바모일(C1-4 알킬), 카복시, 카복시(C1-4 알킬) 또는 (C5-10 헤테로아릴)(C1-4 알킬)이거나, R2 및 R3이 함께 C3-7 사이클로알킬을 형성하고;R 2 and R 3 are each independently hydrogen, C 1-4 alkyl, hydroxy (C 1-4 alkyl), carbamoyl (C 1-4 alkyl), carboxy, carboxy (C 1-4 alkyl) or (C 5-10 heteroaryl) (C 1-4 alkyl) or R 2 and R 3 together form C 3-7 cycloalkyl;
    R4는 수소 또는 카복시(C1-4 알킬)이고;R 4 is hydrogen or carboxy (C 1-4 alkyl);
    R5는 (C1-4 알킬)티오이고;R 5 is (C 1-4 alkyl) thio;
    R6 및 R7은 각각 독립적으로 C1-6 알킬이고;R 6 and R 7 are each independently C 1-6 alkyl;
    R8 및 R9는 각각 독립적으로 수소, 히드록시, 할로겐 또는 C1-4 알콕시이고;R 8 and R 9 are each independently hydrogen, hydroxy, halogen or C 1-4 alkoxy;
    Q는 C5-10 아릴이고;Q is C 5-10 aryl;
    n은 0 내지 3의 정수인 것인 화합물 또는 이의 약학적으로 허용 가능한 염.n is an integer of 0 to 3 or a pharmaceutically acceptable salt thereof.
  3. 제1항에 있어서,The method of claim 1,
    R1은 히드록시, 카복시 또는 히드록시설포닐메틸인 것인 화합물 또는 이의 약학적으로 허용 가능한 염.R 1 is hydroxy, carboxy or hydroxysulfonylmethyl or a pharmaceutically acceptable salt thereof.
  4. 제1항에 있어서,The method of claim 1,
    R2 및 R3은 각각 독립적으로 수소, 카복시, 메틸, 이소부틸, 카바모일메틸, 카복시메틸, 카복시에틸, 히드록시메틸, 이미다졸릴메틸, 인돌릴메틸 또는 에틸이거나, R2 및 R3이 함께 사이클로프로필을 형성하는 것인 화합물 또는 이의 약학적으로 허용 가능한 염.R 2 and R 3 are each independently hydrogen, carboxy, methyl, isobutyl, carbamoylmethyl, carboxymethyl, carboxyethyl, hydroxymethyl, imidazolylmethyl, indolylmethyl or ethyl, or R 2 and R 3 are Together to form cyclopropyl; or a pharmaceutically acceptable salt thereof.
  5. 제1항에 있어서,The method of claim 1,
    R4는 수소, 카복시메틸 또는 카복시에틸인 것인 화합물 또는 이의 약학적으로 허용 가능한 염.R 4 is hydrogen, carboxymethyl or carboxyethyl, or a pharmaceutically acceptable salt thereof.
  6. 제1항에 있어서,The method of claim 1,
    R5는 메틸티오, 에틸티오 또는 디메틸아미노인 것인 화합물 또는 이의 약학적으로 허용 가능한 염.R 5 is methylthio, ethylthio or dimethylamino or a pharmaceutically acceptable salt thereof.
  7. 제1항에 있어서,The method of claim 1,
    R6 및 R7은 모두 부틸 또는 에틸인 것인 화합물 또는 이의 약학적으로 허용 가능한 염.R 6 and R 7 are both butyl or ethyl or a pharmaceutically acceptable salt thereof.
  8. 제1항에 있어서,The method of claim 1,
    R8 및 R9는 각각 독립적으로 수소, 히드록시, 메톡시, 메틸, 에틸, 플루오로, 클로로, 니트로, 시아노, 아미노, 메틸아미노, 에틸아미노, 디메틸아미노, 아세틸, 카복시, 카바모일, 메틸카바모일, 디메틸카바모일, 카바모일옥시, 메틸카바모일옥시, 디메틸카바모일옥시, 메틸설포닐옥시, 설파모일옥시, 메틸설파모일옥시 또는 디메틸설파모일옥시인 것인 화합물 또는 이의 약학적으로 허용 가능한 염.R 8 and R 9 are each independently hydrogen, hydroxy, methoxy, methyl, ethyl, fluoro, chloro, nitro, cyano, amino, methylamino, ethylamino, dimethylamino, acetyl, carboxy, carbamoyl, methyl Carbamoyl, dimethylcarbamoyl, carbamoyloxy, methylcarbamoyloxy, dimethylcarbamoyloxy, methylsulfonyloxy, sulfamoyloxy, methylsulfamoyloxy or dimethylsulfamoyloxy, or a pharmaceutically acceptable thereof salt.
  9. 제1항에 있어서,The method of claim 1,
    Q는 페닐, 피리딘, 피리미딘 또는 티오펜인 것인 화합물 또는 이의 약학적으로 허용 가능한 염.Q is phenyl, pyridine, pyrimidine or thiophene, or a pharmaceutically acceptable salt thereof.
  10. 제1항에 있어서,The method of claim 1,
    상기 화합물은The compound is
    1) 2-(((3,3-디부틸-7-메틸티오-1,1-디옥시도-5-페닐-2,3,4,5-테트라하이드로벤조[b][1,4]티아제핀-8-일)메틸)아미노)아세트산;1) 2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo [b] [1,4] Thiazin-8-yl) methyl) amino) acetic acid;
    2) 3-(((3,3-디부틸-7-메틸티오-1,1-디옥시도-5-페닐-2,3,4,5-테트라하이드로벤조[b][1,4]티아제핀-8-일)메틸)아미노)프로판산;2) 3-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo [b] [1,4] Thiazin-8-yl) methyl) amino) propanoic acid;
    3) 2-(((3,3-디부틸-7-메틸티오-1,1-디옥시도-5-페닐-2,3,4,5-테트라하이드로벤조[b][1,4]티아제핀-8-일)메틸)아미노)숙신산;3) 2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo [b] [1,4] Thiazin-8-yl) methyl) amino) succinic acid;
    4) (S)-2-(((3,3-디부틸-7-메틸티오-1,1-디옥시도-5-페닐-2,3,4,5-테트라하이드로벤조[b][1,4]티아제핀-8-일)메틸)아미노)프로판산;4) (S) -2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo [b] [ 1,4] thiazepin-8-yl) methyl) amino) propanoic acid;
    5) 2-(((3,3-디부틸-7-메틸티오-1,1-디옥시도-5-페닐-2,3,4,5-테트라하이드로벤조[b][1,4]티아제핀-8-일)메틸)아미노)펜탄디오산;5) 2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo [b] [1,4] Thiazin-8-yl) methyl) amino) pentanedioic acid;
    6) 4-아미노-2-(((3,3-디부틸-7-메틸티오-1,1-디옥시도-5-페닐-2,3,4,5-테트라하이드로벤조[b][1,4]티아제핀-8-일)메틸)아미노)-4-옥소부탄산;6) 4-amino-2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo [b] [ 1,4] thiazepin-8-yl) methyl) amino) -4-oxobutanoic acid;
    7) (R)-2-(((3,3-디부틸-7-메틸티오-1,1-디옥시도-5-페닐-2,3,4,5-테트라하이드로벤조[b][1,4]티아제핀-8-일)메틸)아미노)프로판산;7) (R) -2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo [b] [ 1,4] thiazepin-8-yl) methyl) amino) propanoic acid;
    8) 2-(((3,3-디부틸-7-메틸티오-1,1-디옥시도-5-페닐-2,3,4,5-테트라하이드로벤조[b][1,4]티아제핀-8-일)메틸)아미노)-2-메틸프로판산;8) 2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo [b] [1,4] Thiazin-8-yl) methyl) amino) -2-methylpropanoic acid;
    9) (R)-2-(((3,3-디부틸-7-메틸티오-1,1-디옥시도-5-페닐-2,3,4,5-테트라하이드로벤조[b]1,4]티아제핀-8-일)메틸)아미노)-3-(1H-이미다졸-4-일)프로판산;9) (R) -2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo [b] 1 , 4] thiazepin-8-yl) methyl) amino) -3- (1H-imidazol-4-yl) propanoic acid;
    10) (R)-2-(((3,3-디부틸-7-메틸티오-1,1-디옥시도-5-페닐-2,3,4,5-테트라하이드로벤조[b][1,4]티아제핀-8-일)메틸)아미노)-3-(1H-인돌-2-일)프로판산;10) (R) -2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo [b] [ 1,4] thiazepin-8-yl) methyl) amino) -3- (1H-indol-2-yl) propanoic acid;
    11) (S)-2-(((3,3-디부틸-7-메틸티오-1,1-디옥시도-5-페닐-2,3,4,5-테트라하이드로벤조[b][1,4]티아제핀-8-일)메틸)아미노)-4-메틸펜탄산;11) (S) -2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo [b] [ 1,4] thiazepin-8-yl) methyl) amino) -4-methylpentanoic acid;
    12) (S)-2-(((3,3-디부틸-7-메틸티오-1,1-디옥시도-5-페닐-2,3,4,5-테트라하이드로벤조[b][1,4]티아제핀-8-일)메틸)아미노)펜탄디오산;12) (S) -2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo [b] [ 1,4] thiazepin-8-yl) methyl) amino) pentanedioic acid;
    13) (S)-2-(((3,3-디부틸-7-메틸티오-1,1-디옥시도-5-페닐-2,3,4,5-테트라하이드로벤조[b][1,4]티아제핀-8-일)메틸)아미노)-3-히드록시프로판산;13) (S) -2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo [b] [ 1,4] thiazepin-8-yl) methyl) amino) -3-hydroxypropanoic acid;
    14) 3-((카복시메틸)((3,3-디부틸-7-메틸티오-1,1-디옥시도-5-페닐-2,3,4,5-테트라하이드로벤조[b][1,4]티아제핀-8-일)메틸)아미노)프로판산;14) 3-((carboxymethyl) ((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo [b] [ 1,4] thiazepin-8-yl) methyl) amino) propanoic acid;
    15) 3-(((3,3-디부틸-7-메틸티오-1,1-디옥시도-5-페닐-2,3,4,5-테트라하이드로벤조[b][1,4]티아제핀-8-일)메틸)아미노)펜탄디오산;15) 3-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo [b] [1,4] Thiazin-8-yl) methyl) amino) pentanedioic acid;
    16) 2-(((3,3-디부틸-7-메틸티오-1,1-디옥시도-5-페닐-2,3,4,5-테트라하이드로벤조[b][1,4]티아제핀-8-일)메틸)아미노)-2-옥소아세트산;16) 2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo [b] [1,4] Thiazin-8-yl) methyl) amino) -2-oxoacetic acid;
    17) 1-(((3,3-디부틸-7-메틸티오-1,1-디옥시도-5-페닐-2,3,4,5-테트라하이드로벤조[b][1,4]티아제핀-8-일)메틸)아미노)사이클로프로판카복시산;17) 1-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo [b] [1,4] Thiazin-8-yl) methyl) amino) cyclopropanecarboxylic acid;
    18) 2-(((3,3-디부틸-7-메틸티오-1,1-디옥시도-5-페닐-2,3,4,5-테트라하이드로벤조[b][1,4]티아제핀-8-일)메틸)아미노)-2-옥소에탄술폰산;18) 2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo [b] [1,4] Thiazin-8-yl) methyl) amino) -2-oxoethanesulfonic acid;
    19) 2-(((3,3-디부틸-5-(4-메톡시페닐)-7-메틸티오-1,1-디옥시도-2,3,4,5-테트라하이드로벤조[b][1,4]티아제핀-8-일)메틸)아미노)아세트산;19) 2-(((3,3-dibutyl-5- (4-methoxyphenyl) -7-methylthio-1,1-dioxido-2,3,4,5-tetrahydrobenzo [b ] [1,4] thiazepin-8-yl) methyl) amino) acetic acid;
    20) 2-(((3,3-디부틸-5-(4-히드록시페닐)-7-메틸티오-1,1-디옥시도-2,3,4,5-테트라하이드로벤조[b][1,4]티아제핀-8-일)메틸)아미노)아세트산;20) 2-(((3,3-dibutyl-5- (4-hydroxyphenyl) -7-methylthio-1,1-dioxido-2,3,4,5-tetrahydrobenzo [b ] [1,4] thiazepin-8-yl) methyl) amino) acetic acid;
    21) 2-(((3,3-디부틸-5-(3-메톡시페닐)-7-메틸티오-1,1-디옥시도-2,3,4,5-테트라하이드로벤조[b][1,4]티아제핀-8-일)메틸)아미노)아세트산;21) 2-(((3,3-dibutyl-5- (3-methoxyphenyl) -7-methylthio-1,1-dioxido-2,3,4,5-tetrahydrobenzo [b ] [1,4] thiazepin-8-yl) methyl) amino) acetic acid;
    22) 2-(((3,3-디부틸-5-(4-플루오로페닐)-7-메틸티오-1,1-디옥시도-2,3,4,5-테트라하이드로벤조[b][1,4]티아제핀-8-일)메틸)아미노)아세트산;22) 2-(((3,3-dibutyl-5- (4-fluorophenyl) -7-methylthio-1,1-dioxido-2,3,4,5-tetrahydrobenzo [b ] [1,4] thiazepin-8-yl) methyl) amino) acetic acid;
    23) 2-(((3,3-디부틸-5-(3-플루오로페닐)-7-메틸티오-1,1-디옥시도-2,3,4,5-테트라하이드로벤조[b][1,4]티아제핀-8-일)메틸)아미노)아세트산;23) 2-(((3,3-dibutyl-5- (3-fluorophenyl) -7-methylthio-1,1-dioxido-2,3,4,5-tetrahydrobenzo [b ] [1,4] thiazepin-8-yl) methyl) amino) acetic acid;
    24) 2-(((3,3-디부틸-5-(3-플루오로-4-메톡시페닐)-7-메틸티오-1,1-디옥시도-2,3,4,5-테트라하이드로벤조[b][1,4]티아제핀-8-일)메틸)아미노)아세트산;24) 2-(((3,3-dibutyl-5- (3-fluoro-4-methoxyphenyl) -7-methylthio-1,1-dioxido-2,3,4,5- Tetrahydrobenzo [b] [1,4] thiazepin-8-yl) methyl) amino) acetic acid;
    25) 2-(((3,3-디부틸-5-(4-메톡시페닐)-7-메틸티오-1,1-디옥시도-2,3,4,5-테트라하이드로벤조[b][1,4]티아제핀-8-일)메틸)아미노)-2-옥소에탄술폰산;25) 2-(((3,3-dibutyl-5- (4-methoxyphenyl) -7-methylthio-1,1-dioxido-2,3,4,5-tetrahydrobenzo [b ] [1,4] thiazepin-8-yl) methyl) amino) -2-oxoethanesulfonic acid;
    26) 1-(((3,3-디부틸-5-(3-플루오로-4-메톡시페닐)-7-메틸티오-1,1-디옥시도-2,3,4,5-테트라하이드로벤조[b][1,4]티아제핀-8-일)메틸)아미노)사이클로프로판카복시산;26) 1-(((3,3-dibutyl-5- (3-fluoro-4-methoxyphenyl) -7-methylthio-1,1-dioxido-2,3,4,5- Tetrahydrobenzo [b] [1,4] thiazepin-8-yl) methyl) amino) cyclopropanecarboxylic acid;
    27) 2-(((3,3-디부틸-5-(4-플루오로페닐)-7-메틸티오-1,1-디옥시도-2,3,4,5-테트라하이드로벤조[b][1,4]티아제핀-8-일)메틸)아미노)-2-옥소아세트산;27) 2-(((3,3-dibutyl-5- (4-fluorophenyl) -7-methylthio-1,1-dioxido-2,3,4,5-tetrahydrobenzo [b ] [1,4] thiazepin-8-yl) methyl) amino) -2-oxoacetic acid;
    28) (S)-2-(((3,3-디부틸-5-(4-플루오로페닐)-7-메틸티오-1,1-디옥시도-2,3,4,5-테트라하이드로벤조[b][1,4]티아제핀-8-일)메틸)아미노)프로판산;28) (S) -2-(((3,3-dibutyl-5- (4-fluorophenyl) -7-methylthio-1,1-dioxido-2,3,4,5-tetra Hydrobenzo [b] [1,4] thiazepin-8-yl) methyl) amino) propanoic acid;
    29) (S)-2-(((3,3-디부틸-5-(4-플루오로페닐)-7-메틸티오-1,1-디옥시도-2,3,4,5-테트라하이드로벤조[b][1,4]티아제핀-8-일)메틸)아미노)-3-히드록시프로판산; 및29) (S) -2-(((3,3-dibutyl-5- (4-fluorophenyl) -7-methylthio-1,1-dioxido-2,3,4,5-tetra Hydrobenzo [b] [1,4] thiazepin-8-yl) methyl) amino) -3-hydroxypropanoic acid; And
    30) 1-(((3,3-디부틸-5-(4-플루오로페닐)-7-메틸티오-1,1-디옥시도-2,3,4,5-테트라하이드로벤조[b][1,4]티아제핀-8-일)메틸)아미노)사이클로프로판카복시산으로 구성된 군으로부터 선택되는 것인 화합물 또는 이의 약학적으로 허용 가능한 염.30) 1-(((3,3-dibutyl-5- (4-fluorophenyl) -7-methylthio-1,1-dioxido-2,3,4,5-tetrahydrobenzo [b ] [1,4] thiazepin-8-yl) methyl) amino) cyclopropanecarboxylic acid, or a pharmaceutically acceptable salt thereof.
  11. 제1항 내지 제10항 중 어느 한 항의 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 변비의 예방 또는 치료용 약학적 조성물.A pharmaceutical composition for the prevention or treatment of constipation comprising the compound of any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof as an active ingredient.
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